Treatment approaches for hematologic malignancies evolving

The advent of highly active antiretroviral therapy in 1996 has led to markedly improved survival in HIV-infected individuals. Deaths related to opportunistic infections have greatly decreased, and malignancies are now the leading cause of mortality.

In the pre-HAART era, the administration of even conventional-dose chemotherapy for AIDS-related malignancies, such as lymphoma, was challenging due to the poor hematologic reserve of HIV-infected patients and the frequency of opportunistic infections. This led to the initial strategy of treating patients with dose-reduced chemotherapy. As HIV-related lymphomas are often clinically aggressive, long-term remissions were rarely seen when treated with reduced-dose chemotherapy.

In the era of HAART, standard-dose regimens such as R-CHOP and ABVD are now commonly used to treat lymphoma and Hodgkin’s lymphoma and lead to high remission rates, comparable to patients with lymphoma without HIV infection.

For patients with relapsed non-Hodgkin’s B-cell lymphoma, high-dose chemotherapy followed by autologous stem cell transplantation has been shown to be superior to conventional-dose chemotherapy in randomized trials. However, transplantation is often not offered to patients with relapsed HIV-related lymphomas. This exclusion stems from concerns about the potential for drug interactions between antiretroviral drugs and the agents used in high-dose chemotherapy regimens and fears of overwhelming opportunistic infection during the period of severe myelosuppression.

Amrita Krishnan

Now that many clinical investigators consider HIV to be a manageable chronic illness, this prejudice must be called into question. The solid organ transplant physicians have been among the first to break down this barrier for HIV-infected patients. Some transplant surgeons have even stated, “The HIV patient should be considered no different than any other patient who may have higher transplant risks than the average patient.” Is it time for hematologists-oncologists to cross the transplant barrier for the HIV-infected patient as well?

Feasibility of transplant

Several national and international trials have demonstrated the feasibility of performing hematopoietic stem cell transplant in patients with hematologic malignancy and underlying HIV infection. Our experience at the City of Hope was initiated in 1997 and was recently updated with long-term follow-up on 32 patients with Hodgkin’s or non- Hodgkin’s lymphoma who underwent autologous peripheral blood progenitor cell transplant and demonstrated a two-year overall survival of 81%.

Similarly, the European Group for Blood and Marrow Transplantation reported on retrospective data from 20 centers that included 68 patients with a variety of NHL and Hodgkin’s subtypes. Nonrelapse mortality was only 4.4%, and three-year survival 56.5%. Perhaps the most convincing argument to not deny transplant to HIV-positive patients was the case control study from the EBMT.

This retrospective study included 53 patients with HIV-related Hodgkin’s and NHL. Patients were matched by factors, including histology, disease status at autologous stem cell transplantation and year of autologous stem cell transplantation, and compared with HIV-negative controls. The incidence of relapse, progression-free survival and overall survival were similar in both cohorts.

A similar case-controlled study from our own program confirms these observations. The NIH-NCI supported BMT — Clinical Trials Network (CTN), a national cooperative group of transplant centers in the United States, are opening a prospective study of autologous stem cell transplantation in HIV patients with relapsed lymphoma. This trial should confirm the low transplant-related mortality seen in smaller trials and also provide further insight into the immunologic and virologic effects of transplantation on the HIV virus and its reservoir sites. Ultimately, if this trial confirms observations in the United States and Europe, autologous stem cell transplantation should be accepted as a standard of care for appropriate patients with HIV-related lymphomas.

Future direction

What should be our future directions? A case report published in The New England Journal of Medicine provided a glimpse of the potential of hematopoietic stem cell transplant. Hutter reported on a 40-year-old man with acute myeloid leukemia and a 10-year history of HIV infection. The patient underwent an allogeneic stem cell transplantation with peripheral blood stem cells from an HLA-matched donor who was homozygous for the CCR5 delta 32 allele. Specifically, the donor’s cells lacked the CCR5 chemokine receptor, which can be a portal of entry of the R5 type of HIV virus into cells.

Stephen J. Forman

Antiretroviral therapy was stopped after transplant, and the patient remained with undetectable HIV viral loads in the blood. This was the first experience to demonstrate that hematopoietic stem cell transplant could also be the ultimate way to control HIV infection. Of course, the allogeneic approach is limited by the rarity of this genetic mutation (1% in whites), as well as the toxicity of allogeneic transplantation.

There may be other ways of obtaining stem cells that are HIV resistant that may be less toxic and more widely applicable than the unrelated donor approach.

We have tested one such approach that involves genetic transduction of the patient’s own stem cells with small interfering RNAs that reduce CCR5 cellular expression, as well as inhibiting HIV intracellular replication. These stem cells are then transplanted back into the patient after myeloablative chemotherapy. This approach, piloted in five patients, had low toxicity and led to low level durable engraftment of these genetically modified stem cells.

Future studies will address how to achieve higher levels and post-transplant expansion of these genetically HIV-resistant stem cells with the ultimate goal of being able to stop antiretroviral therapy. In short, the future holds the potential to control or perhaps even cure HIV infection with hematopoietic stem cell transplantation.

Amrita Krishnan, MD, FACP, is Director, Multiple Myeloma Program and Associate Director, Medical Education & Training in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Comprehensive Cancer Center, Duarte, Calif.

Stephen J. Forman, MD, is Chair of the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope Comprehensive Cancer Center Duarte, Calif., and a member of the HemOnc Today Editorial Board.

For more information:

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• Hutter G. N Engl J Med. 2009;360:692-698.
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