What is ibrutinib?
Ibrutinib is a tyrosine kinase inhibitor originally FDA-approved in 2013, but more recently approved for chronic graft-versus-host disease (cGVHD) in 2017. Ibrutinib irreversibly binds to Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK).
How does ibrutinib work?
BTK signaling is activated by the B-cell receptor and causes B-cell proliferation and survival. ITK signaling is essential for activation of T-cell subsets. By inhibiting BTK and ITK, ibrutinib inhibits both B- and T-cell function, which are both involved in the pathophysiology of cGVHD.
What is this approved for?
Ibrutinib is approved for patients with cGVHD after failure of at least one prior line of systemic therapy. Its other indications include chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom macroglobulinemia.
What is the basis for this approval?
Ibrutinib was approved in August 2017 based on the results of a phase Ib/II, open-label, multi-center study that included 42 patients. All patients were steroid-dependent or steroid-refractory and had received 1-3 previous therapies for cGVHD. Most patients (86%) had at least two organs involved, with the majority being mouth (86%), skin (81%), or gastrointestinal tract (36%).
Patients were initiated on 420 mg daily and evaluated for overall response, as well as safety and tolerability. Overall response was defined by the 2005 NIH cGVHD response criteria. After a median follow-up of 13.9 months, the overall response rate (ORR) was 67 percent. The ORR was 76 percent in the response-evaluable patients, which excluded five patients who discontinued treatment prior to first assessment. Of the responders, 71 percent derived a sustained response of at least 20 weeks. Similar responses were seen across all organ groups. Median steroid dose decreased among responders from 0.29 mg/kg/day to 0.12 mg/kg/day. Patient-reported symptoms also improved with ibrutinib (Blood 2017;130(21):2243-2250).
How do you administer this drug?
Ibrutinib should be initiated at 420 mg once daily without regard to meals. Therapy should continue until GVHD progression, primary disease recurrence, or unacceptable toxicity.
Are there any premedications needed for ibrutinib?
None required.
What are the common side effects associated with ibrutinib (> or =10%)?
In the clinical trial, the most common toxicities of any grade included fatigue, diarrhea, myalgia, bruising, and nausea. Grade 3 or greater adverse events were less common, but included fatigue, pneumonia, and diarrhea. Dose reductions were required in 31 percent of patients, mostly due to fatigue, and 33 percent of patients discontinued therapy due to an adverse event.
What are the uncommon side effects associated with ibrutinib (less than 10%?)
Less common toxicities include fever, headache, dyspnea, hyperglycemia, hypokalemia, peripheral edema, and atrial fibrillation.
Are there any important drug interactions I should be aware of?
Ibrutinib is a major substrate of CYP3A4 and a minor substrate of CYP2D6, which metabolize the drug into an active metabolite. Therefore, drug concentrations are altered when patients concomitantly receive enzyme inhibitors/inducers. Ibrutinib dose reductions are recommended for patients receiving posaconazole or voriconazole for fungal prophylaxis.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Due to significant hepatic metabolism, dose reductions are recommended for patients with Child-Pugh class A and B impairment and should be avoided in patients with class C impairment. Patients with cGVHD of the liver were not well-represented in the study. No dose adjustments are required for patients with renal insufficiency.
Practical tips
Most insurances will require a prior authorization before covering ibrutinib for cGVHD. Company assistance is available for qualifying patients.
What should my patients know about ibrutinib?
Patients should report any bleeding, shortness of breath, or heart palpitations while taking ibrutinib. They should also report any worsening symptoms associated with their GVHD. Responses to therapy may be seen as soon as 30 days. Patients should be aware that drug interactions are common, and they should report any new medications to the treatment team.
What useful links are available regarding ibrutinib?
* https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf
* https://www.imbruvicahcp.com/
Any ongoing clinical trials related to ibrutinib for cGVHD?
A randomized phase III study, iNTEGRATE, is currently enrolling, which is investigating the use of ibrutinib in combination with corticosteroids for first-line management of cGVHD. More information is available at https://clinicaltrials.gov.
ADAM MELARAGNO, PHARMD, BCOP, is Clinical Pharmacy Specialist, Blood and Marrow Transplant, University of Rochester Medical Center, Rochester, N.Y. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as a Pharmacy Forum column co-editor.
Pharmacy Forum
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