HHV-8 Linked to New Type of AIDS- Related Lymphoma

VANCOUVER, BC--Human herpesvirus-8 (HHV-8), also known as Kaposi'ssarcoma-associated herpesvirus or KSHV, appears to be linked tothe development not only of Kaposi's sarcoma (KS) but also toa newly identified type of AIDS lymphoma, Alexandra Levine, MD,said at an educational symposium at the 11th International Conferenceon AIDS.

Cytokine production also appears to be an important factor inboth KS and AIDS lymphomas, added Dr. Levine, head of the Departmentof Hematology, University of Southern California.

New Picture of Kaposi's Sarcoma

Certain HLA types such as HLA-DQ1 are highly associated with KSin HIV-infected persons, Dr. Levine said in her review of currentknowledge of KS pathogenesis. Hormonal factors may also have arole, since KS is basically a disease of men. "Over the courseof HIV infection, about 40% of gay or bisexual men will be diagnosedwith KS, as opposed to 11% of heterosexual men and 2% of women,"she said. This might reflect sexual exposure to HHV-8.

The HIV tat gene may be the initiating factor transforming a normalmesenchymal cell, presumably of endothelial vascular origin, intoa tumor phenotype, Dr. Levine said. HIV also induces inflammatorycytokine production by infected lymphocytes and monocytes.

"The growth of the tumor is augmented by the inflammatorycytokines made by HIV-infected cells. Once the KS cell exists,it is able to make its own growth factors in an autocrine fashion,"she said.

Treatment Options for KS

Treatment options for KS vary because the disease is variable.In some patients, no initial treatment is required. "Waitfor a month or two and note the pace of the individual's diseasebefore beginning treatment," Dr. Levine advised. However,she warned that, "there is no such thing as one lesion."Kaposi's sarcoma is nearly always disseminated by the time ofinitial presentation, even though only one or two lesions maybe visible.

If the disease is progressive or the patient is uncomfortablewith a lesion for cosmetic or other reasons, the first optionis local treatment. This may include intralesional vinblastine(0.1 to 0.2 mg) or vincristine (0.1 mg).

"Those treatments hurt," Dr. Levine said. "As oncologists,we are trained never to extravasate those agents, which is exactlywhat we are doing here. You must warn the patient about the effects.The injection site will fester and form a scab. When the scabfalls off, most of the time there is normal skin underneath."

Other options for localized treatment include intralesional interferon-alfa(1 million units), liquid nitrogen, laser therapy, or radiation."Be careful with radiation," Dr. Levine cautioned. "Normalskin fibroblasts are exquisitely sensitive to radiation in HIV-infectedpeople. We start with 150 to 180 rad/day, treat for 5 days andstop, wait a week or two, then treat again if needed."

Extensive Disease

Extensive disease can be treated with intravenous interferon-alfaor chemotherapy. Dr. Levine advised against using interferon-alfaas a single agent for extensive disease due to the high dosesneeded (36 million units/day). The other approach is interferon-alfawith antiretro-viral therapy. "We have seen nice partialremissions with ddI [didanosine, Videx] and 1 million units/dayof interferon-alfa," Dr. Levine said.

Indications for chemotherapy include rapidly progressing disease(more than 10 new lesions per month), pulmonary KS, symptomaticvisceral disease, or lymphedema, particularly on an extremity.The standard chemotherapy regimen has been ABV (Adriamycin, bleomycin,vincristine), with a response rate of 50% to 75%.

The most promising new chemotherapy approaches for extensive KSare iposomal doxorubicin, with a reported response rate of 43%;liposomal daun-orubicin (DaunoXome), with a reported responserate of 28%; and paclitaxel (Taxol).

The liposomal formulations provide more drug into the KS cellsat lower systemic concentrations and thus are associated withreduced toxicity. However, liposomal agents can occasionally causeback pain, chest tightness, and flushing during the infusion,Dr. Levine said.

This pain may be due to excretion of the liposomes through thekidney. The treatment is to stop the infusion and start it againmuch more slowly after the pain resolves, she advised.

Low-dose paclitaxel (100 mg/m²) given over 3 hours every2 weeks has produced good response rates after three doses inpatients with recurrent disease. Dr. Levine said that the effectwas particularly dramatic in patients with severe lymphedema.

Unlike Kaposi's sarcoma, AIDS-related lymphomas occur in all HIV-infectedpopulation groups as a late manifestation of HIV. "Like KS,lymphomas may also arise as an indirect consequence of cytokines,"Dr. Levine said. IL-6 and IL-10 induced by HIV cause proliferationand stimulation of B lymphocytes. Epstein-Barr virus (EBV) isalso involved in B cell proliferation.

In the setting of B cell proliferation for a decade or more, agenetic error such as a translocation may occur, with the specifictype of genetic "accident" determining which kind oflymphoma will develop, she said. Immunoblastic lympho-ma appearsto be driven by EBV alone, while small non-cleaved lymphoma isdriven by c-myc, and diffuse large-cell lymphoma by BCL-6.

She said that M-BACOD appears to be the treatment of choice forAIDS-related non-Hodgkin's lymphoma and that low-dose treatmentis as effective as standard-dose treatment, with significantlyless hematologic toxicity.

Primary Effusion Lymphoma

A newly described form of lymphoma, called primary effusion lymphoma(PEL, or body cavity-based lymphoma), has recently been notedin patients with HIV. "These cases rarely have tumor massesbut, rather, present with effusions such as ascites or pericardialeffusions," Dr. Levine said.

These primary effusion lymphomas are B-cell tumors by gene rearrangementbut often lack B-cell markers on the surface. HHV-8 and EBV areboth present, and there are a few case reports already of bodycavity lymphomas associated with HHV-8 and EBV in non-HIV-infectedindividuals. Survival is very short, about 2 to 5 months evenwith chemotherapy, Dr. Levine noted.

Things to Come?

Researchers following HIV-infected patients long-term are seeingHodgkin's disease, anal cancers, oropharyngeal cancers, seminomas,myeloma, and melanomas in these patients. "This may be anindication of what will occur as people with HIV live longer becauseof antiretro-viral therapy, and prevention and treatment of opportunisticinfections," Dr. Levine predicted.

SIDEBAR

New Treatment for IDS Lymphoma Under Study

Dr. Alexandra Levine (see article above) reported at the Van-couverAIDS Conference that mitoguazone dihydrochloride (MGBG), an agentbeing tested for non-Hodgkin's lymphoma and other cancers, mayplay a role in treating AIDs-related lymphomas. The new drug isbeing developed by Ilex Oncology Inc., headquartered in San Antonio.

Dr. Levine reported on 55 patients with AIDS-related lymph-oma,all of whom had failed to respond to or had relapsed followingother cancer treatment.

Of 43 evaluable patients, 10 (23%) had a complete or partial responseto MGBG, and the lymphoma was stabilized in 9 others (20%), Dr.Levine said.

The researchers believe that further study of MGBG, as monother-apyor in combination with other agents, is warranted in patientswith newly diagnosed AIDS-related lymphomas.