1. Fuerst, Mark L.

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SAN DIEGO-Treatment with ibrutinib results in clinically meaningful, durable responses in patients who experience chronic graft versus host disease (GVHD) after stem cell transplantation that is not resolved by corticosteroid treatment, according to a new study presented at the American Society of Hematology annual meeting (Abstract LBA-3).

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Two-thirds of the patients who experienced chronic GVHD responded to ibrutinib, and 71 percent showed sustained improvements with ibrutinib over a 5-month period.


"This is a very high response rate. These data are remarkable, and ibrutinib appears to exceed the therapeutic benefits of other agents. I think clinicians will find these data support the use of ibrutinib in patients with steroid refractory chronic GVHD who currently suffer a range of symptoms that can be chronic and debilitating," said lead author David Miklos, MD, of Stanford University.


Ibrutinib & GVHD Research

Chronic GVHD is a serious complication of allogeneic stem cell transplantation. Immune-suppressing corticosteroid medications are the standard treatment for GVHD, but they do not benefit all patients.


Both B cells and T cells play a role in the pathophysiology of chronic GVHD. In preclinical models, ibrutinib reduced the severity of chronic GVHD through its inhibition of Bruton's tyrosine kinase and interleukin-2-inducible T-cell kinase.


Ibrutinib has recently been granted a breakthrough therapy designation for chronic GVHD after failure of one or more lines of systemic therapy. This designation was supported by early data from a phase II study that evaluated the efficacy and safety of ibrutinib in patients with chronic GVHD who are in need of additional therapy.


Miklos presented the final results of this phase II study, which included 42 patients, median age 56 years, who had received three or fewer prior regimens for chronic GVHD and had either more than 25 percent body surface area erythematous rash or an NIH mouth score greater than 4. They were treated with daily ibrutinib 420 mg until chronic GVHD progression or unacceptable toxicity.


Median duration of chronic GVHD before study entry was 13.7 months. Median number of prior regimens was two.


At a median follow-up of 14 months, overall response rate was 67 percent, with 21 percent complete response. Some 71 percent of patients showed a sustained response of 20 or more weeks and 48 percent responded for 32 or more weeks.


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


Overall, three-quarters of responders had corticosteroid doses less than 0.15 mg/kg per day during the study. Five responders discontinued corticosteroid therapy while in response.


Median overall clinician-assessed chronic GVHD severity score decreased from 7 at baseline to 4 at week 25 and 3 at week 49. A corresponding decrease in median patient-assessed overall chronic GVHD score from 7 at baseline to 5 at week 25 and 4 at week 49 was reported.


Improvement in Lee Chronic GVHD Symptom score was reported for 12 (43%) and 17 (61%) of 28 responders by month 6 and overall, respectively, compared with 1 (11%) of 9 non-responders by month 6 and overall.


Of 36 patients with two or more involved organs, 20 patients (56%) showed a response in two or more organs; of 12 patients with three or more involved organs, five patients (42%) showed a response in three or more organs.


Analysis of soluble plasma factors associated with inflammation, fibrosis, and chronic GVHD from all treated patients showed a significant decrease over time with ibrutinib, including soluble CD25 and IP-10 levels, which are implicated in chronic GVHD-related inflammation.


The most common adverse events were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Grade 3 or higher adverse events occurring in more than three patients included pneumonia, fatigue, and diarrhea.


These adverse events are consistent with those in prior ibrutinib studies and in patients with chronic GVHD and underscore the importance of actively monitoring and managing any adverse events when prescribing ibrutinib, Miklos said.


Serious adverse events occurred in 22 patients (52%); grade 3 or higher serious adverse events were reported in 17 patients (40%), including pneumonia, septic shock, and pyrexia. There were two fatal events (multilobar pneumonia and bronchopulmonary aspergillosis).


Five patients discontinued therapy for progressive chronic GVHD and 14 patients for adverse events, including fatigue and pneumonia. Twelve patients (29%) continued ibrutinib; their treatment duration ranges from 5.6 months to 24.9 months.


Miklos said 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 anti-tumor cytotoxic T cells intact," he explained. "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."


Researchers are currently recruiting patients for several additional trials to further investigate the use of ibrutinib in preventing or treating GVHD and to compare it to other agents.


Mark L. Fuerst is a contributing writer.