In a first, the US Food and Drug Administration (FDA) has approved a drug for use in  patients who develop the life-threatening condition of chronic graft-vs-host disease (cGVHD) after having undergone a hematopoietic stem cell transplant (HSCT). The approval was received on August 2nd, 2017. This condition develops in about 30% to 70% of patients who undergo HSCT, which is a standard treatment for various leukemias and lymphomas.

“Patients with cGVHD who do not respond to other forms of therapy — typically corticosteroids to suppress their immune system — now have a treatment option specifically indicated to treat their condition,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. This condition develops in about 30% to 70% of patients who undergo HSCT, which is a standard treatment for various leukemias and lymphomas.

Chronic GVHD usually begins later after transplant and lasts longer than acute GVHD. Patients with Chronic GVHD may present with a wide variety of symptoms. Skin rash and/or mouth sores are among the most common initial signs of the disease. The rash is often slightly raised and may be itchy. Unlike acute GVHD, chronic GVHD can cause damage in the glands that produce tears in the eyes and saliva in the mouth resulting in dry eyes or a dry mouth. Patients may have mouth ulcers causing pain while eating, skin rashes, or liver inflammation. Chronic GVHD can also cause many other problems. One such problem is formation of scar tissue in the skin (cutaneous sclerosis) and joints. Another such problem is damage to air passages in the lungs (bronchiolitis obliterans syndrome).

Patients who have had a blood or marrow stem cell transplant from another person (allogeneic transplant) can get chronic GVHD. Patients who have had acute GVHD have a greater risk of developing chronic GVHD. Older patients, patients who received a peripheral blood (instead of bone marrow) transplant, and patients who had a mismatched or unrelated donor have a greater risk of chronic GVHD.

The exact cause of chronic GVHD is not known. It is likely that it is a complicated disorder due to difficulty of the new immune system (from the donor) maturing in the host (the patient). Chronic GVHD is most often diagnosed by the characteristics of the rash or by changes in the eyes or mouth. Chronic GVHD can also be diagnosed by characteristic symptoms or signs involving many other organs and sites including joints and connective tissues, lungs, esophagus, stomach, intestines, liver, and vagina, among others. The diagnosis is usually confirmed by pathology findings. If the skin is not affected, other tests can be used to confirm the diagnosis in other organs and sites.

The drug recently approved is ibrutinib (Imbruvica, Pharmacyclics), which is already marketed for use in several hematologic malignancies, including chronic lymphocytic leukemia and small lymphocytic lymphoma, as well as mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma. “This approval highlights how a known treatment for cancer is finding a new use in treating a serious and life-threatening condition that may occur in patients with blood cancer who receive a stem cell transplant,” Dr Pazdur added. Commenting on the new approval, James Ferrara, MD, DSc, the Ward-Coleman Chair in Cancer Medicine and director of the Hematologic Malignancies Translational Research Center at the Tisch Cancer Institute at Mount Sinai, New York City, said: “This is an important advance and great news for our patients, because it is the first drug to be approved for this difficult condition.”

“Chronic graft-versus-host disease is a major complication of bone marrow and stem cell transplants that can be fatal when it does not respond to therapy, and a number of trials have failed in the past,” he said. “The response rate here is very high and extremely encouraging. Further trials will test whether ibrutinib can be used as primary therapy at the onset of disease, perhaps providing even better responses.”

The data to support the new indication come from a single-arm trial of 42 patients with cGVHD whose symptoms persisted despite standard treatment with corticosteroids, the FDA noted.  Most patients’ symptoms included mouth ulcers and skin rashes, and more than half of these patients had two or more organs affected by cGVHD.  Details from this trial were presented at the 2016 annual meeting of the American Society of Hematology.

“Ibrutinib resulted in a meaningful and sustained clinical response in patients who have failed at least one prior treatment for chronic GVHD,” said lead investigator, David Miklos, MD, PhD, an associate professor of medicine at Stanford University in California. At a median follow-up of 14 months, the overall response rate was 67%, and 21% of patients achieved a complete response. In addition, 48% of responders showed a sustained response, with some responses lasting more than 6 months. Yi-Bin Albert Chen, MD, director of clinical research, Bone Marrow Transplant Program at Massachusetts General Hospital in Boston, noted that the rationale for using ibrutinib is based on the T-cell immunomodulating and B-cell inhibitory activities of ibrutinib and that multiple trials involving patients with B-cell malignancies have established safety. “The overall response rate of 67% is quite compelling,” he said, noting that “a large phase 3 randomized study combining ibrutinib with corticosteroids for the initial therapy of chronic GVHD is planned.”

In its press release, the FDA noted that common side effects of ibrutinib in patients with cGVHD include fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia, and pneumonia. The agency also noted that serious side effects of ibrutinib include hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, second primary malignancies, and metabolic abnormalities (tumor lysis syndrome). Women who are pregnant or breast-feeding should not take the drug because it may harm a developing fetus or a newborn baby.

As always, readers of this blog are highly encouraged to read the complete sources/references listed below thoroughly and in full to contextualize the complete information provided. Additionally, interested parties on this topic important topic about the serious problem of opioid diversion within our health systems should seek further information on this topic from scientific and medical information readily available in the public domain as well as speak with their health care provider.


  • Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia [published online December 6, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1509388