A Breakthrough Drug Facilitates Safer Bone Marrow Transplants

Within the walls of the Center for Clinical Sciences Research, scientists are hard at work developing life-saving treatments for patients with blood and bone marrow cancers.

Since 1987, Stanford has performed more than 7,000 adult bone marrow transplants, long considered the gold standard for treating people with these cancers. However, a potentially serious complication of bone marrow transplantation is graft versus host disease (GVHD).

GVHD is caused when immune cells from a donor start attacking the normal tissues of a recipient. This can lead to painful, debilitating problems in organs from the skin and mouth to the liver and lungs, including itchy rashes, nausea and vomiting, muscle weakness, and breathing difficulty.

For those needing a bone marrow transplant, the ideal option is to find a donor within the patient’s family, but the odds for a match of antigens between family members are at best only one in four. The next best option is a transplant of cells from an unrelated donor, known as a hematopoietic cell transplant. However, the risk for GVHD increases with unrelated donors.

Corticosteroids were the conventional treatment for GVHD, but the long-term use of steroids has many side effects, and GVHD frequently re-emerges when steroids are stopped.

Researchers had been working for years to find a more reliable treatment than steroids, and they found it in ibrutinib, the first drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of GVHD.

We'd been looking for a long time for therapies to get patients with chronic GVHD off steroids

A team led by David Miklos, MD, PhD, associate professor of blood and marrow transplantation, contributed greatly to the development of ibrutinib.

“We’d been looking for a long time for targeted effective therapies to get patients with chronic GVHD off steroids. But other drugs, even those that showed early promise, all ended up failing to show benefit in randomized clinical trials,” Miklos says.

Miklos discovered that B lymphocytes — one type of immune cell — are critical to the development of chronic GVHD. Blocking B cell activity, he hypothesized, could prevent or treat the disease. Ibrutinib — a drug first developed to treat B cell cancers and already approved for multiple cancer types — was able to potently deplete B cells from a hematopoietic cell transplant donor. Miklos approached Pharmacyclics, the Sunnyvale-based company that makes ibrutinib, about launching a clinical trial of the drug for GVHD; the company agreed.

Miklos and his colleagues presented favorable results of that trial at an annual meeting of the American Society of Hematology. On the heels of that research, the FDA fast-tracked its approval process, and in August 2017 the FDA approved ibrutinib for the treatment of patients with chronic GVHD who have failed at least one systemic treatment.

More recent insights come from senior scientist Bita Sahaf, PhD, who has worked in the Miklos lab since 2007. Sahaf presented the mechanism for ibrutinibchronic GVHD during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation in early 2018.

“Our research is focused on B and T cells, two important components of the immune system. The overall research goal is the characterization of adaptive B and T cell immune responses that cure cancer while avoiding GVHD,” Miklos explains.

Now, Miklos and his colleagues are working on a randomized placebo-controlled trial of 185 patients to see if ibrutinib is effective in patients with earlier stages of GVHD. They expect to have results by the end of 2019.

“Perhaps most exciting, the Stanford Bone Marrow Transplant program has initiated its own clinical trial to see if ibrutinib immediately following transplant can prevent chronic GVHD from developing months later,” Miklos says.