On August 2, 2017, the U.S. Food and Drug Administration (FDA) expanded the indication for ibrutinib – the treatment of chronic graft-versus-host disease (cGVHD) after failure of first-line or multiline therapy in The Food and Drug Administration (FDA) expanded the indication for ibrutinib to treat adult patients with chronic graft versus host disease (cGVHD) after failure of first-line or multiline therapy.
Irutinib was the first drug approved for the treatment of chronic graft versus host disease, which until then had been treated primarily with glucocorticoids, but in a subset of patients, hormone therapy was not effective. There have been no good treatment options for this group of patients.
What is chronic graft-versus-host disease?
Graft-versus-host disease is a serious and potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Graft-versus-host disease occurs when cells from a hematopoietic stem cell transplant attack healthy cells in the patient’s tissue. Depending on the time of onset and clinical presentation, graft-versus-host disease can be classified as acute (aGVHD) or chronic (cGVHD). Chronic graft-versus-host disease can also be classified as limited or extensive, depending on the organ involved. Unlike acute graft-versus-host disease, chronic graft-versus-host disease is often extremely slow to damage tissues and organs and has complex symptoms that can manifest in the skin, eyes, mouth, intestines, liver, and lungs. The incidence of chronic graft-versus-host disease is approximately 30% to 70% in all patients who receive hematopoietic stem cell transplants.
Glucocorticoids are the first-line treatment for chronic graft-versus-host disease. If chronic graft-versus-host disease does not improve after 2 weeks of hormone 1 mg/(kg-d) combined with immunosuppression, or if glucocorticoid dosage exceeds 0.5 mg/(kg-d) for 4 to 8 weeks without improvement or if hormone cannot be reduced to 0.5 If the glucocorticosteroid dosage exceeds 0.5 mg/(kg-d) for 4 to 8 weeks without improvement or if the hormone cannot be reduced to less than 0.5 mg/(kg-d), then chronic graft-versus-host disease is hormone-refractory.
What is ibrutinib?
Irutinib is an oral kinase inhibitor that was previously approved for the treatment of non-Hodgkin’s lymphoma (NHL, including chronic lymphocytic leukemia and small lymphocytic lymphoma), NHL carrying 17p deletion, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), marginal zone lymphoma (MZL). Both T and B cells play an important role in the development of chronic graft-versus-host disease. Erutinib attenuates chronic graft-versus-host disease by inhibiting Bruton tyrosine kinase in B cells and interleukin 2-induced T-cell kinase in T cells.
Evidence of efficacy: 67% improvement in chronic graft-versus-host disease symptoms where hormonal control was not effective
The approval of ibrutinib was based primarily on data from 1 single-arm clinical trial that enrolled 42 patients with chronic graft-versus-host disease whose symptoms persisted despite standard glucocorticoids. Symptoms in the majority (88%) of patients included oral ulcers and rashes, and more than 50% had two or more organs affected by chronic graft-versus-host disease. In this trial, chronic graft-versus-host disease symptoms improved in 67% of patients. In 48% of the patients in the trial, improvement in symptoms lasted for five months or longer.
Adverse effects: need to be alert for second primary malignancy and tumor lysis syndrome
Common adverse reactions to ibrutinib in the treatment of chronic graft-versus-host disease include, among others, fatigue, bruising, diarrhea, thrombocytopenia, muscle cramps, mouth ulcers, nausea, bleeding, anemia, and pneumonia.
It is important to note that serious adverse reactions to ibrutinib include severe bleeding, infection, hemocytopenia, cardiac arrhythmias (atrial fibrillation), hypertension, second primary malignancy, and tumor lysis syndrome. Pregnant or breastfeeding women should not take ibrutinib because it may cause harm to the fetus or newborn.
How is ibrutinib used to treat chronic graft-versus-host disease?
According to the approved product insert, the recommended use and dosage of ibrutinib for the treatment of chronic graft-versus-host disease is as follows:
The recommended use of ibrutinib for the treatment of chronic graft-versus-host disease is as follows
- Recommended dose: 420 mg orally daily until progression of chronic graft-versus-host disease, or recurrence of malignancy, or unacceptable toxicity. Medical evaluation is required before discontinuing the drug when the patient no longer requires treatment for chronic graft-versus-host disease.
- The recommended dose is 140 mg daily for mild hepatic impairment (Child-Pugh class A) and 70 mg daily for moderate hepatic impairment (Child-Pugh class B).
Irutinib was launched in China in 2017, but the indications currently approved in China do not include treatment of chronic graft-versus-host disease.
Chronic graft-versus-host disease is a major cause of hematopoietic stem cell transplant failure and long-term patient death, and long-term hormone therapy may bring adverse effects, as well as a subset of patients who are not sensitive to hormone therapy. The approval of ibrutinib brings new hope for the treatment of chronic graft-versus-host disease, and hopefully more targeted drugs like ibrutinib will be available in the future to bring longer-lasting disease control to patients with chronic graft-versus-host disease.