Lung Injury Limits Transplant Success|
Blood stem cell (a.k.a bone marrow) transplant is the only treatment option for patients with many conditions affecting the immune system, such as aplastic anemia, leukemia and sickle cell anemia, said Dr. Kenneth Cooke at a Contemporary Clinical Medicine/ Great Teachers Grand Rounds held in Lipsett Amphitheater on Sept. 9.
Before patients receive a transplant, high doses of chemotherapy or radiation are used to destroy their existing immune systems. Bone marrow stem cells from a donor are then used to seed a new immune system in the recipient. If all goes well, the donor cells multiply into a fully functioning immune network that protects the patient against disease, explained Cooke, professor of pediatric oncology at Johns Hopkins School of Medicine and director of the Pediatric Bone Marrow Program at Hopkinsí Sidney Kimmel Comprehensive Cancer Center.
Sometimes, however, the immune cells mistake the cells of their new host for a disease-causing invader. The result is graft vs. host disease (GVHD), a potentially life-threatening condition where the donor cells—the graft—attack the patient cells—the host. GVHD is “always a risk unless the donor and host are identical twins,” Cooke said.
Lung injury is also a major problem that continues to limit successful outcomes after bone marrow transplantation (BMT). Lung inflammation can occur early after BMT or later and may be infectious or non-infectious in origin. “When lung complications occur within the first 3 to 4 months after BMT and develop in the absence of infection, they fall under the umbrella of idiopathic pneumonia syndrome [IPS],” he said.
Historically, patients with IPS are treated with supportive care and steroids. However, these treatments have been ineffective. “The median time from diagnosis to death is 14 days, so many of these patients would go to the intensive care unit and not come back to us,” he said.
Cooke believes many cases of IPS can be traced to damage of endothelial cells, which line the inside of blood vessels. This endothelial cell layer is responsible for several functions, including controlling blood pressure and allowing white blood cells to pass back and forth from the blood vessels to the lymphatic system.
In mouse studies, Cooke observed that animals with GVHD developed inflammation in their lungs. He believes that T-cells, a type of white blood cell, could trigger an immune response that attacks the endothelium in the lungs. An inflammatory protein called TNF alpha may be involved in the response. This immune attack may cause injury to the lungs as a manifestation of GVHD.
Cooke said observations made in the laboratory regarding the role of TNF alpha in non-infectious lung injury after BMT led to a clinical trial of etanercept, an FDA-approved drug that blocks TNF alpha. It’s used to treat rheumatoid arthritis and psoriasis in patients with IPS.
In the drug’s first trial, 3 pediatric patients with severe IPS who required mechanical breathing machines received 2 doses of the drug per week over a 4-week period. Remarkably, each patient responded to treatment and was able to come off of the breathing machine. Unfortunately, each patient ultimately died from other complications, but IPS was not the cause of death.
Cooke and his team at the University of Michigan next combined efforts with colleagues at Dana-Farber Cancer Institute to conduct an early phase, prospective clinical trial on 15 adult and pediatric BMT recipients with IPS. Nearly 70 percent of patients responded to the combination of steroids and etanercept. Cooke’s research team took advantage of blood and lung samples to further their understanding of what causes IPS in humans.
With a growing body of laboratory data and the encouraging early responses seen in initial clinical trials, Cooke and his colleagues then launched 2 national multi-center clinical trials for patients with IPS: 1 trial in pediatric patients and 1 in adult patients over age 18.
The pediatric trial closed early due to effectiveness. Cooke said 40 patients enrolled in the study. They received the drug with steroids or a placebo twice a week for 4 weeks. He hoped that more than half of patients would respond to treatment. However, “we had a 70 percent response rate for efficacy. So it led to early closure.”
The other trial opened in 2007. Originally, 120 adult patients were to be enrolled. Unfortunately, this trial closed early because it couldn’t recruit enough participants. “This was a tough pill to swallow,” he said.
Cooke still thinks etanercept can be used for patients post-transplant. “I think it’s a safe and efficacious therapy and I think our data in pediatrics supersedes anything else in the published literature,” he added.
Despite his best efforts, “lung dysfunction remains a problem after transplant.” His lab continues to seek insights into the underpinnings of IPS, especially early indicators that will predict who is at risk of developing IPS and who might ultimately respond to anti-TNF therapy.