Understanding Bone Marrow Transplantation. Clinical and Personal Perspectives

Posted By SHL Librarian

Presented by David Miklos, MD, PhD
Associate Professor of Medicine, Blood and Marrow Transplantation

and Bonnie Willdorf
Author, Dancing with Cancer: Maladies and Miracles in Stem Cell Transplantation
February 7, 2018

A bone marrow transplant can save the lives of people diagnosed with cancer. But there’s a challenge that comes with it.

People may have to live with medical complications of the transplant ranging from mildly uncomfortable to severe or even life-threatening.

It’s a tough trade-off, said David Miklos, MD, PhD, a specialist in bone marrow transplantation and other cancer treatments.

“You can do these life-saving therapies,” Dr. Miklos said in a recent lecture at the Stanford Health Library. But the patient has to be a willing partner in choosing treatment and handling the long-term challenges to their quality of life. “I think the patients have to help really guide their treatment path,” he said.

Partnership with patients

Dr. Miklos spoke about the medical aspects of bone marrow with Bonnie Willdorf, who wrote a book about her experience with her husband Barry when he underwent a transplant for leukemia. He lived for more than 8 years after his diagnosis as he went through 2 bone marrow transplants.

“The hardest and most rewarding time in my marriage was caregiving for Barry,” she said, quoting from her book, Dancing with Cancer: Maladies and Miracles in Stem Cell Transplantation. She added, “We worked hard at our relationships with the doctors, nurses, and other staff here at Stanford—and it paid off.”

Cancer treatments have expanded greatly in recent years. Previously, for more than 20 years,  chemotherapy was a mainstay of treatment focused solely on killing cancer cells. Then researchers also found ways to drive a person’s own immune system to fight the cancer.

“In the last 5 years, cancer therapy has been exploding,” said Dr. Miklos, who is also the medical director of the Stanford Cellular Therapeutics and Transplantation Laboratory.  “In the last 2 years, I get out of bed in the morning and you can’t keep me at home,” he said, “because there are so many new therapies, and so many ways to help people.”

Combining old with new

Some of the newer therapies combine old-school chemotherapy with newfound ways to direct the body’s own immune system to fight cancer. The combination of both can be a powerful, if tricky, process.

To explain how the 2 methods work together, Dr. Miklos described the history of cancer treatments developed over time:

  • While chemotherapy has been used for the last 50 years, it still plays a role in many cancer treatments. “It’s a poison,” Dr. Miklos said. Its side effects can make patients sick, but it’s effective against certain cancers, particularly lymphoma and multiple myeloma.
  • Over time, doctors developed a way to deliver high-dose chemotherapy, followed by a “rescue” procedure that provides “blood seeds,” hematopoietic stem cells that restore the patient’s blood and immune system. The procedure extracts the patient’s healthy stem cells from bone marrow, delivers the chemotherapy, and then returns the healthy cells to the patient to regrow the immune system. This is known as an autologous (bone marrow) transplant.
  • In the 1990s, drugs called monoclonal antibodies debuted. They can attach to cancer cells, either creating a target for attack, or even bringing chemotherapy drugs to “the scene of the crime,” Dr. Miklos said.
  • In the last few years, new antibodies called “checkpoint inhibitors” (aimed at PD-1, PD-L1 and other co-stimulatory targets with blocking antibodies) have been used to make the surface of cancer cells vulnerable to drug treatment.
  • Some treatments also use the body’s immune system to get rid of cancer, often in combination with chemotherapy.
  • First, to prepare for the immune therapy, chemotherapy is given to attack and destroy cancer cells.
  • Then doctors double-down on the cancer by doing a kind of bone marrow transplant called allogeneic. That means the transplanted cells come from a separate histocompatible donor rather than the patient themselves. The transplanted cells may kill any remaining cancer cells.
  • The transplanted cells are also going to view the cancer patient’s blood cells as foreign, and attack to destroy them. In effect, the patient’s own immune system is wiped out and replaced with a new transplanted one.

New immune system

Transplanting another person’s bone marrow stem cells amounts to transplanting an entire immune system into the cancer patient. “Allogeneic means somebody else’s immune system is dropped into your body,” Dr. Miklos said.

While this can be an effective way to cure cancer, it comes with the potential for many complications.

“You have to rebuild the immune system in what may be a 60-year-old individual,” Dr. Miklos said. Until their transplanted immune systems have grown to be strong—which takes time—patients are vulnerable to infections and other complications.

“They come right out of our hospital and they’re in this dirty world, and you see them wearing masks and washing their hands, and trying to stay from the problems of infections,” Dr. Miklos said.

There’s no guarantee, after enduring that difficult adjustment, that the transplant will bring a cure. “You could go through that entire process and still have relapse,” Dr. Miklos said. Despite the challenges of this procedure, it has become a common therapy for advanced cancer. Stanford expects to do at least 300 allogeneic transplants this year, and more than 500 cellular therapies this year.

Finding donors

Traditionally, allogeneic transplants have been done using donations from the siblings of cancer patients, when possible. Although sisters and brothers aren’t an exact genetic match for the bone marrow stem cells, they share enough traits to make this kind of donation desirable. If no siblings are available, the transplant can also be done using matched unrelated donors.

Whether siblings or not, the differences between the donor’s and the patient’s cells make for a tremendous challenge. Not only is it uncertain whether the transplant will cure the cancer—it’s also uncertain whether the patient’s body can adjust to the transplanted cells.

The transplanted cells include white blood cells (lymphocytes), called B cells and T cells. Their function is to recognize any foreign substances that might be a threat to the body and destroy them.

Once the lymphocytes are transplanted into the cancer patient, they may view the patient’s normal body tissues—the skin, the gut, the liver—as foreign targets to attack. That can lead to a condition called graft-versus-host disease, or GVHD.

“If it weren’t for graft-versus-host disease, everybody would want an allogeneic transplant, because it’s highly effective at killing chemorefractory cancer,” Dr. Miklos said.

Balancing benefit with risk

After an allogeneic transplant, cancer relapse rates are in the range of 15 percent in people who had myeloid and lymphoid cancers, Dr. Miklos said. That means the rate for curing those kinds of cancers is 85 percent or more.

But the problems linked to rebuilding the immune system after the transplant—and avoiding infections, and complications in the skin, gut, or lungs—can be daunting.

“You transplant the immune system and it sees the whole body as foreign,” Dr. Miklos said.

In the first 3 months after an allogeneic transplant, the new immune system is not fully working so GVHD the patient must be protected from infections. After that, the challenge is to manage the growth of an entirely new immune system in the patient. That means dealing with the potential for chronic GVHD.

Graft-versus-host disease

If the new immune system begins attacking body tissues, a patient can end up with complications that include white skin spots, changes to toenails and fingernails, hair loss, and mouth sores. The white spots (called sclerosis) on the skin may look like hard white blisters. If this sclerosis spreads to internal organs and tissues, it can affect breathing and even walking.

The benefits and risks of allogeneic transplant can be summarized like this: It may cure the cancer, but it also can cause this graft-versus-host disease. For many people, it’s a tough choice.  “This is the yin and the yang,” Dr. Miklos said, “the good and the bad.”

Letting patients decide

Over the years he has done allogeneic transplants, there’s one thing he’s learned about making a decision on treatment: It’s all about the patient. It is crucial to make sure each patient is informed on the benefits and risks of a transplant. All too often, doctors have emphasized the potential for a cure and underestimated the challenges of the side effects.

“It took me a while to figure this out—25 years,” Dr. Miklos said. When talking to patients about the pros and cons, he said, “You have to have a partnership, and you have to have meaning in what you do.”

He added, “Likewise, I think patients have to help really guide their treatment path.”

Bonnie Willdorf, who spoke with Dr. Miklos, said she and her husband Barry took time to ponder the risks and benefits of a bone marrow transplant, when his previous treatment stopped working for chronic lymphocytic leukemia. It wasn’t an easy call, because Dr. Miklos (who was Barry’s doctor) was honest about the risks.

Exhausting but rewarding

Barry chose the transplant, and they never looked back. Eventually, he underwent a second transplant after the first transplant needed a boost. Some days were just plain exhausting, draining, and unpredictable.

“Dr. Miklos has warned us that things happen, but of course we thought we would be different and Barry would just sail through,” Bonnie said, quoting from the book she wrote together with Barry. “Denial is very strong and helpful…”

In all, Barry lived more than 8 years after his diagnosis.

“Not all of that time was difficult,” Bonnie said, quoting from the book.  “We had many rich experiences and a lot of quality of life.”

Speaking up

She urged other people with cancer, and their caregivers, to spend time and effort building a good relationship with doctors, nurses, and other staff during treatment. It’s important to speak up if the patient or caregiver feels anything is wrong or needs attention, she said

At the same time, she and her husband learned that there are limits to what can be done.

“We all want doctors to know everything and to be able to fix it,” she said. “This is never going to happen. They do their best, and that’s all we can hope for.”

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David Miklos, MD, PhD

Stanford Blood and Marrow Transplantation Program