This story is part of a series that explores the success of City of Hope’s bone marrow transplant program, which recently performed its 15,000th transplant.
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“I still see their faces.”
Joseph Alvarnas, M.D., associate clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation, is thinking about the patients he encountered in the AIDS ward decades ago as a young medical student in San Francisco. He remembers watching the monthly honor roll on local TV news, which displayed photos of those who'd succumbed to the disease. “In many months, I knew them all,” he recalled sadly.
Everything changed in 1996 with the arrival of effective antiretroviral therapy (ART), which represented the first set of treatments that could reduce the level of HIV in the blood below detectable levels, in effect allowing the patients’ T cell immunity to recover to normal levels. As a result, people who are HIV-positive can manage their condition with as little as one pill a day and look forward to a long life.
But they're not cured.
The antiretroviral breakthrough didn't eliminate HIV, or some of the other problems it can create. HIV can still potentially damage the heart, lungs and kidneys, and it still increases the risk of many types of cancer. For example, HIV-infected patients have a risk of developing non-Hodgkin’s lymphoma more than 24 times greater than the general population.
As people with HIV began to live longer, a growing number of HIV-related lymphomas (HRL) and other cancers appeared. With the increase came a new question: Could the standard treatments for these diseases — like stem cell transplants for lymphoma, for example — be effective in patients affected by HIV?
But they're not cured.
The antiretroviral breakthrough didn't eliminate HIV, or some of the other problems it can create. HIV can still potentially damage the heart, lungs and kidneys, and it still increases the risk of many types of cancer. For example, HIV-infected patients have a risk of developing non-Hodgkin’s lymphoma more than 24 times greater than the general population.
As people with HIV began to live longer, a growing number of HIV-related lymphomas (HRL) and other cancers appeared. With the increase came a new question: Could the standard treatments for these diseases — like stem cell transplants for lymphoma, for example — be effective in patients affected by HIV?
Getting Smart
At first, said Alvarnas, the answer was no.
“The early transplant experience, prior to the availability of ART in the United States and Europe [with HIV patients], was abysmal, because of infections that set in,” recalled Alvarnas, pointing out that the transplant procedure temporarily diminished patients' immune systems. “We had to get smart about what to do, like finding the right antibiotics to protect them. We had to think about doing this carefully, managing the infections and other complications.”
Careful thinking and “getting smart” paid off, especially with autologous (from the patients' own stem cells) transplants for HRL. Where once in the early days of the HIV epidemic the very idea was considered “crazy,” by 2016 Alvarnas was able to report the results of a key study that followed 40 such patients:
"Overall survival for patients with HIV infection after transplant is comparable to that seen in people who were not HIV-infected," Alvarnas wrote. “Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection."
“The early transplant experience, prior to the availability of ART in the United States and Europe [with HIV patients], was abysmal, because of infections that set in,” recalled Alvarnas, pointing out that the transplant procedure temporarily diminished patients' immune systems. “We had to get smart about what to do, like finding the right antibiotics to protect them. We had to think about doing this carefully, managing the infections and other complications.”
Careful thinking and “getting smart” paid off, especially with autologous (from the patients' own stem cells) transplants for HRL. Where once in the early days of the HIV epidemic the very idea was considered “crazy,” by 2016 Alvarnas was able to report the results of a key study that followed 40 such patients:
"Overall survival for patients with HIV infection after transplant is comparable to that seen in people who were not HIV-infected," Alvarnas wrote. “Based on our data, autologous stem cell transplant should be considered the standard of care for patients with HIV-related lymphomas for the same indications and under the same circumstances that we would use it in patients without HIV infection."
A New Standard of Care
Within a year, many groups in the international medical community had done their own research and come to the same conclusion, leading Alvarnas and his City of Hope colleagues John Zaia, M.D., the Aaron D. Miller and Edith Miller Chair in Gene Therapy and director of the Center for Gene Therapy, and Stephen Forman, M.D., the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, to declare in a subsequent paper: “Autologous HCT is now the standard of care for patients with HIV-related lymphomas who otherwise meet standard transplant criteria.”
The best results were achieved in patients whose lymphoma had responded to chemotherapy and whose HIV was under control through combination antiretroviral therapy.
It's important to strike the right balance between the chemotherapy required for transplant and the patient's anti-HIV drugs. Alvarnas said this requires “due diligence,” and he recommends bringing in an expert — a pharmacist with HIV training, for example — to choose the appropriate drugs. One of his goals is to ultimately standardize those drug combinations so everyone treating HRL — not just a handful of specialized facilities — can employ them.
The best results were achieved in patients whose lymphoma had responded to chemotherapy and whose HIV was under control through combination antiretroviral therapy.
It's important to strike the right balance between the chemotherapy required for transplant and the patient's anti-HIV drugs. Alvarnas said this requires “due diligence,” and he recommends bringing in an expert — a pharmacist with HIV training, for example — to choose the appropriate drugs. One of his goals is to ultimately standardize those drug combinations so everyone treating HRL — not just a handful of specialized facilities — can employ them.
A Tantalizing Goal
Though the evidence is not yet as extensive as with autologous transplants, it now appears that some patients with HRL may benefit from allogeneic (donor) stem cell transplants as well. And here, a tantalizing goal — the potential elimination of HIV — may be in sight.
That's because we now have two people — Timothy Brown, the so-called “Berlin patient” from 10 years ago, and a more recent, unnamed patient in London — whose HIV disappeared after undergoing transplants from donors. Both patients have stopped taking their antiretrovirals, and they are considered “cured,” though we still have much to understand about how best to translate this into the quest for a cure in other patients.
One possibility lies with the CCR5 receptor in CD4+ immune cells. HIV uses that receptor to enter and attack the immune system. But some people have a CCR5 mutation that blocks that pathway. Both the Berlin and London patients received donated stem cells with the CCR5 mutation, and clinical trials are underway to see if this is a potential way to stop HIV in its tracks. Drugs like Selzentry may replicate the actions of that mutation, and work is also going forward to create genetically modified stem cells which, when transplanted, would deny HIV entry into patients’ immune systems.
“I'm excited by the potential demonstrated by the Berlin and London patients,” said Alvarnas, who added that “two are better than one,” because it's less likely that the results were a fluke. “We've got to try and replicate that.”
“The holy grail,” he says, “is to find a cure.”
That's because we now have two people — Timothy Brown, the so-called “Berlin patient” from 10 years ago, and a more recent, unnamed patient in London — whose HIV disappeared after undergoing transplants from donors. Both patients have stopped taking their antiretrovirals, and they are considered “cured,” though we still have much to understand about how best to translate this into the quest for a cure in other patients.
One possibility lies with the CCR5 receptor in CD4+ immune cells. HIV uses that receptor to enter and attack the immune system. But some people have a CCR5 mutation that blocks that pathway. Both the Berlin and London patients received donated stem cells with the CCR5 mutation, and clinical trials are underway to see if this is a potential way to stop HIV in its tracks. Drugs like Selzentry may replicate the actions of that mutation, and work is also going forward to create genetically modified stem cells which, when transplanted, would deny HIV entry into patients’ immune systems.
“I'm excited by the potential demonstrated by the Berlin and London patients,” said Alvarnas, who added that “two are better than one,” because it's less likely that the results were a fluke. “We've got to try and replicate that.”
“The holy grail,” he says, “is to find a cure.”
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