Treating Human Immunodeficiency Virus–Related Lymphoma

A Conversation With Alexandra Levine, MD, MACP




What matters is that [HIV-infected] patients are treatable and curable to the same extent, or very similar extent, as non–HIV-infected patients with the same types of lymphoma.
— Alexandra Levine, MD, MACP

Alexandra Levine, MD, MACP, is Professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, Duarte, California, and has been on the front lines of the AIDS epidemic from the beginning—before the disease even had a name. Dr. Levine spoke with The ASCO Post about cancers caused by infectious organisms, advances in the treatment of human immunodeficiency virus (HIV)-related lymphomas, and the future of HIV/AIDS research.

Infections and Cancer

Please talk about the relationship between infectious organisms and cancer.

Germs can cause cancer. About 25% of cancers in resource-poor areas and 5% in resource-rich areas of the world are attributable to organisms. In November 2016, the U.S. Department of Health & Human Services 14th Report on Carcinogens named seven new carcinogens, five of which were organisms: human T-lymphotropic virus, Epstein-Barr virus, Kaposi’s sarcoma–associated herpesvirus (also known as human herpesvirus type 8), Merkel cell polyomavirus, and HIV. In addition, the International Agency for Research on Cancer defines 10 organisms as well established carcinogens in humans, with HIV considered a cofactor for the development of cancer.

HIV is clearly an indirect cause of cancer, simply by causing severe depression of the immune system, and the cancers that arise in that setting are commonly caused by opportunistic organisms taking advantage of the host’s weakened resistance. But recently, biologic mechanisms have been described indicating that HIV itself may directly cause the lymphomas as well, which is very intriguing.

HIV-Related Cancers

What cancers are HIV-positive individuals at risk for?

Combination antiretroviral therapy has significantly reduced the risk of AIDS-defining cancers—Kaposi’s sarcoma, high-grade B-cell lymphoma, and cervical cancer—but this risk still remains elevated compared to the population as a whole. Even with an undetectable viral load, or with CD4 cell counts above 500 cells/dL, the risk of lymphoma is nearly threefold that expected in the general population, for example.

However, HIV-infected individuals are also at risk for additional cancers that were not originally thought to be connected to this epidemic. They are primarily cancers related to organisms. Human papillomavirus, for example, causes anal and oropharyngeal cancers in addition to cervical cancer, and HIV-positive patients are at increased risk for all of them. Hodgkin lymphoma, which is caused by Epstein-Barr virus in this setting, is also clearly increased in HIV-infected people. And if you are HIV-infected and also infected by hepatitis C or B, there’s a greater risk of liver cancer than without the underlying HIV.

None of these cancers were originally thought to be related to HIV or immunosuppression, but we’re now seeing statistical increases in these tumors among HIV-infected patients. Although combination antiretroviral agents are remarkably effective, even if someone’s CD4 cells become elevated beyond 500 cells/dL and their viral load becomes undetectable, they still have immune defects that have not been corrected by those drugs and are still at risk for some of these organism-caused cancers. They are also at increased risk of tobacco-associated lung cancer.

Complexity of Medicine

It seems like every time you make a breakthrough in treating the disease, it reveals deeper complexities.

That’s what all of medicine is like. I think, in a certain way, we are unknowable. It’s unbelievably complicated; every system and molecule are interacting with every other molecule. So, at the same time you solve a problem, you’re likely to find another problem that needs to be solved. That’s just medicine. That’s what keeps it interesting.

Impact of HIV Infection on Treatment

How does lymphoma treatment differ for HIV-infected patients?

What matters is that these patients are treatable and curable to the same extent, or very similar extent, as non–HIV-infected patients with the same types of lymphoma. That’s a big deal.

First, we have learned what treatment decisions are likely to lead to better outcomes. When you start chemotherapy for lymphoma, for example, it is extremely important to start combination antiretroviral therapy at the same time. We were initially afraid that combining the two regimens might be too toxic, but time has shown that it is critical to use the antiretrovirals right from the beginning of chemotherapy. This has been shown to increase overall survival, particularly in patients with < 100 CD4 cells.

Second, rituximab (Rituxan) is extremely useful in these patients and must be part of the chemotherapy regimen. There were early concerns that rituximab was associated with an increased risk of infection, but they have been disproven, and oncologists need to be aware that rituximab is extremely important for getting the patient into remission.

Third, in diffuse large B-cell lymphoma, current data indicate that continuous infusion over 96 hours is more effective than receiving 1 big dose every 3 weeks.1,2 Infusional therapy with the R-EPOCH regimen (rituximab, etoposide, prednisone, vincristine, and doxorubicin) has been shown to be superior to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP (rituximab plus CHOP) in retrospective analyses.

Another recent advance is the opportunity to decrease the number of cycles required for an optimal outcome. Typically, chemotherapy for diffuse large B-cell lymphoma consists of 6 cycles (approximately 6 months), but the short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) regimen, developed and studied by investigators at the National Cancer Institute (NCI), has changed this approach.3 After baseline positron-emission tomography/computed tomography (PET/CT) scans, patients were given two cycles of chemotherapy, followed by a repeat PET/CT scan. If the scan was negative, they were given one more cycle to consolidate, for a total of only three cycles. In patients with PET positivity, three additional cycles were given. Approximately 80% of patients required only 3 cycles of therapy.

The progression-free survival rate was 84%, and overall survival was 68%. Patients with CD4 cell counts < 100 cells/dL at study entry were more likely to succumb, however. Combination antiretroviral therapy was withheld in these NCI studies, until the completion of all chemotherapy. Given our recent experience, the strong recommendation is to start antiretrovirals concurrently with chemotherapy, in an attempt to prevent potentially life-threatening opportunistic infections and death, particularly in patients with CD4 cell counts < 100 cells/dL.

Treating Relapse

What about treatment for HIV-infected individuals with lymphoma who relapse?

For noninfected patients with relapsed/refractory diffuse large B-cell lymphoma, standard therapy would include high-dose chemotherapy followed by autologous stem cell transplant. With this technique, around 60% to 70% of HIV-negative patients will develop long-term disease-free survival. HIV-infected patients in this setting, however, have often been excluded from transplant, which was thought to be too risky.

A recent study of 40 patients led by City of Hope, as part of the AIDS Malignancy Consortium and the Blood and Marrow Transplant Clinical Trials Network has shown that outcomes of autologous stem cell transplant in patients with persistent or relapsed AIDS-related lymphoma are similar to those in noninfected patients.4 AIDS patients were able to mobilize stem cells similarly to noninfected patients, and the time to recovery of neutrophils and platelets was also similar. More importantly, overall survival and progression-free survival rates at 2 years were 83% and 77%, respectively. Thus, these AIDS patients with relapsed or persistent lymphoma are still potentially curable with stem cell transplant. That’s a big deal.

Looking Ahead

Where is the research headed?

A huge area of research relates to the possibility that underlying HIV infection might actually be cured, and several techniques, including gene therapy with manipulation of hematopoietic stem cells, have been studied. A well-described “Boston patient” was HIV infected and developed acute myeloid leukemia, for which he underwent stem cell transplant. By happenstance and luck, the donor had a mutation in CCR5, which is one of the molecules needed by HIV to infect CD4 cells. The CCR5-delta 32 mutation rendered this patient resistant to further HIV, and he is believed to have been cured of his HIV. This area is under active investigation. ■

Disclosure: Dr. Levine reported no potential conflicts of interest.

References

1. Little RF, Pittaluga S, Grant N, et al: Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: Impact of antiretroviral therapy suspension and tumor biology. Blood 101:4653-4659, 2003.

2. Barta SK, Xiaonan X, Wang D, et al: Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: A pooled analysis of 1546 patients. Blood 122:3251-3262, 2013.

3. Dunleavy K, Little RF, Pittaluga S, et al: The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood 115:3017-3024, 2010.

4. Alvarnas JC, Le Rademacher J, Wang Y, et al: Autologous hematopoietic cell transplantation for HIV-related
lymphoma: Results of the BMT CTN 0803/AMC 071 trial. Blood 128:1050-1058, 2016.



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