Updated May 6, 2015: Editor’s note – It is with sadness that we report that Greg Grappone, who kindly shared his story with us, died on May 1, 2015.
Greg Grappone just wants to be a regular dad.
The 35-year-old found out the day after his daughter, Briar, was born in 2012 that he would need a blood stem cell transplant for his cutaneous T-cell lymphoma, a type of blood cancer that attacks the skin.
Although many patients living with CTCL don’t need a transplant, Grappone’s cancer had become particularly aggressive. He had painful rashes covering nearly 80 percent of his body; it hurt him to hold his newborn daughter.
Grappone’s transplant, using cells donated by his sister, went well. And it seems to have cured his cancer.
But six months after the procedure, his legs started to swell, the first clue that his sister’s immune cells were attacking not only his disease but healthy parts of his body, too, a condition known as chronic graft-vs.-host disease, or GVHD.
Stem cell transplants’ power to cure disease comes from the ability of the donor cells to recognize cancerous cells as foreign and then attack them. But too often, the new cells don’t know to limit their attack to cancer and wreak havoc on other organs as well. The rogue immune cells can attack the skin, digestive system, liver, lungs, connective tissues and eyes. Doctors used to think that a modest amount of GVHD was an important sign that the transplant was working, but recent studies show that this potentially dangerous side effect may not be necessary after all.
GVHD is not rare. Up to 70 percent of transplant recipients develop acute GVHD, which crops up within the first few months of treatment, and 40 percent get chronic GVHD, the form that appears more than 100 days post-transplant. As the name implies, the chronic condition can last for years — or a lifetime — and its symptoms range from mildly annoying to disabling to life-threatening.
Now, more than two years post-transplant and a year and a half into his debilitating journey with GVHD, Grappone still can’t be the father to Briar he wishes he could be. He’s reliant on a walker or wheelchair due to the body stiffness, swelling and constriction of the muscles in his torso and limbs. He can only walk for about 60 seconds at a time because his breathing is so restricted.
“For the first two years of [Briar’s] life I couldn’t interact with her like a normal father. I can’t run over and grab her and pick her up,” Grappone said. Even before the GVHD developed, he had to be careful about interacting with his daughter in the months following his transplant to protect his weakened immune system from infections. (Although as a small upside, he was relieved of diaper-changing duty.)
And as a harsh reminder of his original cancer symptoms, the GVHD itself has caused his skin to be sensitive and painful at times.
“It’s tough to look at your daughter and tell her, ‘Don’t hug Daddy too hard,’” he said.
Even now that the sunburn-like symptoms have subsided, “story time with Daddy is not just story time,” he said. Instead it means asking Briar to wait while he slowly makes his way over to the couch and gets his legs into a position that’s comfortable for reading. It also means trying to remind his exuberant 2-year-old not to jump on the sofa while he’s getting settled.
“You just want to be a normal father, to put your daughter on your shoulders and run around,” Grappone said. “But that’s just not an option.”
When chronic GVHD is particularly severe, as in Grappone’s case, that can cause real hardship, said Dr. Mary Flowers, a GVHD expert at Fred Hutchinson Cancer Research Center and Grappone’s doctor at Seattle Cancer Care Alliance, Fred Hutch’s treatment arm. Patients come in for their transplant, a potentially lifesaving treatment, with the hope of curing their cancer — and they accept the risks associated, Flowers said. Unfortunately, while she and her colleagues can make good guesses as to which patients will get GVHD, they can’t predict who may end up with the most severe forms of the disease, as Grappone did.
“It can be frustrating for patients who find themselves cured of their primary disease but are now living with a chronic illness with a profound impact on their quality of life — it is like trading one disease for another,” Flowers said.
Although Grappone said Flowers told him that certain aspects of his disease are among the worst she’s ever seen, he counts himself lucky that the disease hasn’t affected his internal organs. He’s had friends with that type of GVHD, the kind that attacks the liver or lungs and can lead to irreversible damage. Lung complications can be especially difficult to treat and may advance before patients even notice symptoms.
Many aspects of the disease are maddeningly mysterious for patients and their care providers, Flowers said, but emerging research advances in the field have given her hope that the tide could soon turn. In the past few years, the field has seen technological advances that could help scientists answer heretofore baffling questions — questions like, why do some patients develop life-threatening symptoms while some escape with only a mild rash? Can we head off GVHD right when it starts to brew, before it causes major damage? Are there ways to predict which treatments will work best? Can we separate the lifesaving powers of transplantation from its damaging side effects?
The steroid prednisone is the standard first treatment for patients with acute or chronic GVHD and for many, that’s enough. Grappone has been taking prednisone since his symptoms started, he said, but it’s not working to fully knock down the disease.
Flowers and her team have treated Grappone with a variety of other drugs, a procedure known as extracorporeal photopheresis (a light-based therapy for the blood that sometimes stimulates cells to fight the GVHD) and interleukin-2 (a drug to dampen the “bad” donor immune cells) to no avail. He’s currently trying bortezomib, an anticancer drug that’s now being tested in experimental settings against GVHD.
That medication roulette is a major frustration for Dr. Stephanie Lee, an oncologist and clinical researcher at Fred Hutch who studies chronic GVHD. If prednisone doesn’t work, clinicians are often stumped as to what to do next.
“You have to make your best guess,” Lee said. “I wish I had a better way of seeing a person with graft-vs.-host disease and being able to do some kind of test to tell me, OK it’s this category of medicines that would be more effective for this person.”
Fred Hutch researchers are working to develop such tests to help guide treatment decisions, Lee said. Their goal is to knock down GVHD not only to alleviate suffering for patients like Grappone but to be able to offer the curative potential of stem cell transplants to more patients in the first place.
“For many diseases [transplantation] really is the best chance of a cure, it’s just that getting to the cure is still dangerous,” Lee said. “So if you can remove some of that danger, I think that we would be able to transplant more people and, hopefully, cure more people and not lose people from that complication.”
Fred Hutch is headquarters to the Chronic Graft-versus-host Disease Consortium, a large network of researchers funded by the National Institutes of Health working to better understand and treat the disease. The consortium recently completed a study of 1,000 people living with chronic GVHD that revealed new risk factors for the disease and biomarkers, or biological signposts, to help detect, diagnose and predict patient outcome.
The study found that cancer patients who receive transplants of stem cells taken from a donor’s blood — as Grappone did — are more likely to develop GVHD than patients who get transplants directly from bone marrow. But blood stem cell transplants are still the favored option at SCCA and other top transplant centers, Flowers said, because of their potent curative power.
Transplant doctors have to strike a delicate balance between knocking down the disease and minimizing toxic side effects, and the cells and molecules that battle cancer are intricately linked to those that attack healthy tissues in GVHD. Specifically, the immune cells known as T cells are involved.
“One effective way to fight cancer is to the use the immune system,” Flowers said. “Blood stem cells have more T cells, and that’s important for eradicating the malignancy, but T cells are also involved in development of chronic GVHD.”
Fred Hutch researchers have taken their new knowledge to the laboratory to tweeze apart the T cells that fight cancer from those that trigger GVHD, and their results have already translated into new clinical trials. One such trial spearheaded by Drs. Marie Bleakley and Stanley Riddell uses a transplant in which certain T cells have been sifted out from the donor blood before the procedure — and it’s showing promising results in reducing chronic GVHD while still preventing cancer recurrence (this particular trial studies patients with acute myeloid leukemia).
Lee, Flowers and their colleagues are also conducting several studies testing promising new treatments for chronic GVHD, a next generation of therapies with greater precision to target the disease-causing immune cells. And that’s exactly what the field needs, Lee said.
“If the normal stuff isn’t working, you really need to go outside the box and attack the problem in a different way,” she said. “These targeted agents have the potential to do that.”
Lee is leading two new studies testing drugs called proteasome inhibitors (like bortezomib, Grappone’s current treatment) that block the cellular machinery that degrades unnecessary proteins. The build-up of those proteins causes cells to die. To date, proteasome inhibitors have shown promise for patients with blood cancers. Lee and her colleagues have reason to believe the drugs also could combat the immune cells responsible for GVHD.
Fred Hutch clinical researcher Dr. Marco Mielcarek is conducting research to treat not only transplant patients but their donors. Taking a different tack to prevent GVHD (in this case, acute GVHD), Mielcarek is leading a new study that asks stem cell donors to take a two-week course of a statin, a class of drugs normally used to lower cholesterol.
Researchers have long understood that statins can tamp down the immune system, making the kind of T cells that trigger GVHD “less inflammatory,” Mielcarek said. That work prompted him to look at Fred Hutch’s databases of patient records. In that retrospective study, he and his colleagues found that if stem cell donors were on a statin at the time they donated, the transplant recipients’ likelihood of getting severe acute GVHD was eliminated.
If that result bears up in his current prospective study, in which donors are asked to take atorvastatin, the generic version of the brand-name statin Lipitor, before transplant, it could be a simple but important fix for the most deadly form of acute GVHD, Mielcarek said.
And eliminating GVHD — acute or chronic — is a reasonable goal, he said.
“The common wisdom used to be, and we would even tell that to our patients, ‘Well, we actually want you to get some GVHD — maybe not too much — because it will help to fight your cancer,’” Mielcarek said. “That notion has been called into question at least a little bit recently.”
A recent study led by Fred Hutch researcher Dr. Rainer Storb looked at more than 1,000 patients who’d received “mini-transplants” — a gentler version of transplantation often used for elderly patients. Storb and his colleagues found that contrary to the common wisdom, getting GVHD did not make patients more likely to survive their cancer. In fact, both acute and chronic GVHD were associated with lower survival rates.
Grappone said his doctors in Boston (where he received his transplant before he and his family moved to Seattle) warned him about GVHD, but he wishes he’d had more information about it before it happened to him. He didn’t know how much it could affect his everyday life, even years after transplant.
That surprise is common and difficult to avoid, Flowers said. She agrees that doctors have to educate their patients about the likely effects of transplantation, but it’s also hard for patients to think about the future when they’re staring cancer in the face now. Patients are primarily focused on surviving a disease that could take their lives in the next few months, she said. And even if they hear how common GVHD can be, they may have a hard time believing it will happen to them.
“[Percentages] don’t work on an individual basis,” Flowers said. “Of course patients always hope it’s going to be the best.”
Grappone encourages other patients facing a transplant to do their own research about GVHD ahead of time, to know what they might be getting into.
“If I had known this was a possibility, it would have been another mark in the column of what to do. I’m not saying I wouldn’t have taken the transplant,” Grappone said. “I’m glad I don’t have recurrence of the cancer, but my life is completely different now.”
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.