Ibrutinib Shows Promise in Treating GVHD After Stem Cell Transplant


An FDA-approved blood cancer drug has demonstrated encouraging findings, including an overall response rate of 67%, in treatment of patients with chronic graft-versus-host-disease that was not resolved by corticosteroids.

David Miklos, MD, PhD

An FDA-approved blood cancer drug has demonstrated encouraging findings, including an overall response rate (ORR) of 67%, in treatment of patients with chronic graft-versus-host-disease (cGVHD) that was not resolved by corticosteroids.

In a multicenter study presented as a late-breaker at the 2016 ASH Annual Meeting, ibrutinib (Imbruvica) showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD. In addition, the majority of responders were able to reduce steroid doses to an acceptable minimal level.

Of the 42 participants who experienced GVHD, 67% responded to ibrutinib, and 71% had sustained improvements over a 5-month period. According to the researchers, the results are encouraging for a subset of patients with limited treatment options beyond corticosteroids.

Lead author of the study, David Miklos, MD, PhD, called the findings “remarkable” and said that ibrutinib appears to exceed the therapeutic benefits of other agents.

"This is a very high response rate," said Miklos, associate professor of Blood and Marrow Transplantation at the Stanford University Medical Center. “Clinicians will find these data support the use of ibrutinib in patients with steroid-refractory chronic GHVD, who currently suffer a range of symptoms that can be chronic and debilitating.”

cGVHD is a serious complication of allogeneic stem cell transplantation (ASCT), in which the transplanted stem cells attack the patient’s body, causing symptoms such as rashes, mouth ulcers, dry eyes, gastrointestinal problems, shortness of breath, and decreased mobility in the joints and limbs. Although immune-suppressing corticosteroid meditations are the standard treatment for cGVHD, they do not benefit all patients, Miklos explained.

Ibrutinib is a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor that is used in the post-allogeneic setting for the treatment of chronic lymphocytic leukemia. Preclinical laboratory studies suggested that ibrutinib might also inhibit immune cells involved in cGVHD.

Supported by earlier results of this phase II study presented at ASH, ibrutinib was granted a breakthrough therapy designation by the FDA for cGVHD after failure of 1 or more lines of systemic therapy.

For the multicenter, open-label, phase II study, researchers enrolled 42 patients with steroid dependent/refractory cGVHD following ASCT.

Patients had failed 3 or fewer prior therapies for cGVHD and had either more than 25% body surface area involving an erythematous rash or a National Institutes of Health (NIH) mouth score greater than 4.

Ibrutinib was administered daily at 420 mg until cGVHD progression or unacceptable toxicities. The primary endpoint was cGVHD response based on the 2005 NIH consensus response criteria.

Results showed that 21% of responders had a complete response and 19% had a partial response. Seventy-one percent of the 28 responders had a sustained cGVHD response of at least 5 months.

Furthermore, cGVHD response was observed across multiple organs: 56% (20/25) of patients with 2 or more involved organs at baseline responded in at least 2 organs, and 42% of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and multiple organs suggest that ibrutinib is actually targeting the underlying process of cGVHD and not simply masking the symptoms of cGVHD,” said Miklos.

Patients also had meaningful improvement in their cGVHD symptoms as assessed by Lee Symptom Score improvements of greater than 7 points. Consistent with this improvement, clinician-assessed and patient-reported reductions in overall cGVHD severities were reported throughout the study, as well.

In addition, patients on ibrutinib experienced reductions in corticosteroid doses. Overall, 26 patients achieved corticosteroid doses less than .15 mg/kg daily while on ibrutinib and 5 responders were able to discontinue all corticosteroid treatment.

An analysis of biomarker changes also support the beneficial effect of ibrutinib on cGVHD-related immune cell subsets.

Regarding safety, 45% of participants experienced serious adverse events (AEs) such as pneumonia, septic shock, or severe fever. Additional AEs include fatigue, diarrhea, muscle spasms, nausea, and bruising.

As Miklos reported, however, these side effects are consistent with those previously reported for ibrutinib and those observed in patients with cGVHD on concomitant corticosteroids.

Overall, he added, ibrutinib represents a promising potential new therapy for GVHD.

“By targeting allogeneic B cells and TH2 lymphocytes, ibrutinib is targeting a pathogenic mechanism that we believe causes GVHD, while leaving protective and antitumor cytotoxic T cells intact,” said Miklos. “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.”

Miklos and colleagues are recruiting participants for additional trials that will further investigate the use of ibrutinib in preventing or treating GVHD and compare it with other agents.

Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, California. Abstract LBA3.


View more from the 2016 ASH Annual Meeting

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