FDA Approves First Drug for GVHD After Stem Cell Transplant

Zosia Chustecka   


August 02, 2017

UPDATED August 3, 2017 // 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).

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.

The drug 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."

Approval Based on Small, Single-Arm Trial

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.

In this trial, GVHD symptoms improved in 67% of patients after ibrutinib treatment, and in 48% of patients, the improvement of symptoms lasted for up to 5 months or longer.

Details from this trial were presented at the 2016 annual meeting of the American Society of Hematology and were reported at the time by Medscape Medical News.

"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.

"Patients with multiple organ involvement generally showed responses to two or more organs," said Dr Miklos during his presentation. "They also experienced reductions in corticosteroid doses, and biomarker changes support the clinical effect chronic GVHD immune cell subsets."

Approached for comment, 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.

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