Ibrutinib: A Potential Option for Chronic Graft-vs-Host Disease?

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These data are promising, as they suggest that ibrutinib may offer a new approach for managing this common posttransplant complication.
— David Miklos, MD, PhD

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Currently, there is no U.S. Food and Drug Administration (FDA)-approved therapy for chronic graft-vs-host disease—a life-threatening consequence of stem cell or bone marrow transplant—that has not responded to corticosteroids, but this may be about to change. Ibrutinib (Imbruvica) achieved meaningful responses in patients who developed chronic graft-vs-host disease after transplant and failed to respond to at least one prior treatment, according to results of a multicenter, open-label phase II trial reported at a late-breaking session at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition.1 Based on these promising phase II results, a phase III study is planned to evaluate front-line treatment of chronic graft-vs-host disease with ibrutinib.

“In this study, ibrutinib led to clinically meaningful and sustained responses in patients with [chronic] graft-vs-host disease who failed on at least one prior treatment for graft-vs-host disease,” said lead investigator David Miklos, MD, PhD, of Stanford University School of Medicine, Palo Alto, California.

“Patients with chronic graft-vs-host disease face a challenging treatment journey, with the majority being prescribed steroids, with which long-term use can lead to serious health complications. With no FDA-approved therapies available specifically for chronic graft-vs-host disease, new treatment options are critically needed,” Dr. Miklos stated.

Graft-vs-host disease is the most common cause of morbidity following allogeneic transplant. “Ibrutinib has been granted Breakthrough Therapy status by the FDA for this indication. Ibrutinib is well known for inhibiting Bruton’s tyrosine kinase, a protein that plays a key role in B-cell–receptor signaling and currently an FDA-approved therapy for chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s disease.

What is not as widely known is its role in blocking interleukin-2–inducible T-cell kinase, which is expressed in T lymphocytes. Ibrutinib started out a B-cell cancer drug, and now it’s an immune-modulating agent with promising chronic graft-vs-host disease benefit.

Ibrutinib for Chronic Graft-vs-Host Disease

  • A phase II trial showed encouraging results with ibrutinib in the treatment of chronic graft-vs-host disease that did not respond to corticosteroids.
  • These promising early data need to be replicated in larger phase III trials.

Key Study Findings

The study enrolled 42 patients (with a median age of 56 years) with chronic graft-vs-host disease who failed to respond to at least one prior therapy, including corticosteroids. Patients were treated once daily with ibrutinib at 420 mg orally until progression of graft-vs-host disease or unacceptable toxicity. The baseline characteristics of the patients in this trial are similar to those of patients we see in the clinics, added Dr. Miklos.

Approximately half of the study patients were male, and the median time to diagnosis was 7.6 months after transplant. The median time to initiation of ibrutinib was 13.7 months, and the median number of lines of prior therapy was two.

At a median follow-up of 13.9 months, the overall response rate was 67% (28 of 42 patients), including 22% of patients with a complete response. A total of 80% of patients with two or more organs involved at baseline responded in at least two organs.

Over the course of the study, 61% of responders experienced clinically meaningful improvement in symptoms, as measured by at least a 7-point decrease in the Lee Symptom Scale score (see sidebar). In addition, 62% of responding patients were able to reduce the steroid dose to an acceptable minimal level, and five patients completely discontinued steroids with response. Twelve patients (29%) remained on treatment with ibrutinib at the time of the presentation at the ASH Annual Meeting.

We all hope these data hold up over time and with further testing, but the track record for such studies leading to FDA approval is poor.
— Thomas G. Martin, MD

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Adverse events were as expected with ibrutinib, Dr. Miklos told the audience: fatigue, nausea, diarrhea, muscle spasms, and bruising. Serious adverse events, including pneumonia, septic shock, or severe fever, were reported in 22 patients. Two deaths occurred on the trial.

“These findings underscore the importance of active monitoring and managing any adverse events that develop with ibrutinib,” declared Dr. Miklos.

Mechanism of Action

“Ibrutinib doesn’t simply mask the symptoms of chronic graft-vs-host disease. By targeting allogeneic B cells and T helper 2 lymphocytes, ibrutinib is targeting a pathogenic mechanism that we believe causes graft-vs-host disease while leaving protective and antitumor cytotoxic T cells intact. This is a targeted therapy that does not just bluntly suppress the immune system; it leaves patients better able to fight their cancer as well as viral infections,” explained Dr. Miklos.

What Is the Lee Symptom Scale?

The Lee Symptom Scale is a tool to assess the degree to which a patient is or has been bothered over the past 4 weeks by 30 common symptoms associated with chronic graft-vs-host disease (eg, those affecting skin, eyes/mouth, levels of fatigue, and emotional distress). Each symptom is measured on a scale of 1 to 5, with 1 being “no symptoms/not bothered” to 5 being “extremely bothered” by symptoms. A higher score is correlated with more bothersome symptoms. ■

Lee SF, Cook EF, Soiffer R, et al: Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 8:444-452, 2002.

“There is an urgent need for new effective therapies for patients with steroid-resistant chronic graft-vs-host disease, a condition that can be incapacitating and even fatal when it is not controlled. These data are promising, as they suggest that ibrutinib may offer a new approach for managing this common posttransplant complication,” he stated.

Still Early Data

“The early data for ibrutinib [in chronic graft-vs-host disease] seem exciting and are worthy of watching,” commented Thomas G. Martin, MD, of the University of California San Francisco, Helen Diller Family Comprehensive Center, California, who was not involved in this trial. “However, development of drugs for chronic graft-vs-host disease has been hampered by promising phase I/II data and early enthusiasm, followed by lack of improved efficacy in phase III,” he admitted. “These studies are very difficult to perform, and phase I/II studies are typically done at limited centers with some selection bias. Other inherent bias due to conduct at few centers also can be problematic.”

Dr. Martin concluded: “We all hope these data hold up over time and with further testing, and there are scientific reasons to believe ibrutinib will be a breakthrough drug in chronic graft-vs-host disease, but unfortunately, the track record for such studies leading to FDA approval is poor.” ■

Disclosure: Dr. Miklos has served as a consultant for Pharmacyclics; has received research funding from Pharmacyclics, Kite Pharma, Roche, and Novartis; and has been paid for travel on behalf of Pharmacyclics and Sanofi Oncology. Dr. Martin reported no potential conflicts of interest.


1. Miklos D, Cutler CS, Arora M, et al: Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease after failure of corticosteroids. 2016 ASH Annual Meeting. Abstract LBA3. Presented December 6, 2016.

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Expert Point of View: Kanti R. Rai, MD

Many transplanters will now offer ibrutinib to their patients because this agent is available, approved by the U.S. Food and Drug Administration for other closely related indications, and also serves an important unmet medical need.
— Kanti R. Rai, MD

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