On August 2, 2017, ibrutinib (Imbruvica) was approved for treatment of adult patients with chronic graft-vs-host disease after failure of one or more lines of systemic therapy.^1,2 This is the first U.S. Food and Drug Administration (FDA)-approved therapy for treatment of chronic graft-vs-host disease.

Approval was based on responses in the open-label study PCYC-1129-CA, in which 42 patients with chronic graft-vs-host disease who required additional therapy after failure of first-line corticosteroid therapy received ibrutinib at 420 mg once daily. The median age of study patients was 56 years; 52% were male; 93% were white; and the most common underlying malignancies leading to transplantation were acute lymphocytic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia. The median time since chronic graft-vs-host disease diagnosis was 14 months, the median number of prior chronic graft-vs-host disease treatments was 2 (range = 1–3), and 60% of patients had a Karnofsky performance score ≤ 80. Infection prophylaxis was managed according to institutional guidelines, with 79% of patients receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole derivatives.

Response (using the 2005 National Institutes of Health [NIH] consensus panel response criteria with two modifications to align with the updated 2014 NIH criteria) was observed in 28 patients (67%). The median time to response coinciding with the first scheduled response assessment was 12.3 weeks (range = 4.1–42.1 weeks). Responses were seen in all organs involved with chronic graft-vs-host disease, including skin, mouth, gastrointestinal tract, and liver. Responses of ≥ 5 months were observed in 20 patients (48% of the entire patient group).

How It Works

Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. BTK activity via signaling through the B-cell surface receptor results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. Preclinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.

How It Is Used

The recommended dose of ibrutinib in chronic graft-vs-host disease is 420 mg once daily until chronic graft-vs-host disease progression, recurrence of an underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for chronic graft-vs-host disease, treatment should be discontinued, taking into consideration medical assessment of the individual patient.

Ibrutinib treatment should be interrupted for grade 3 or higher nonhematologic toxicities, grade 3 or higher neutropenia with fever, and grade 4 hematologic toxicities. With resolution of toxicity to grade 1 or baseline status, treatment can be reinitiated at the starting dose. Recommended dose reductions in chronic graft-vs-host disease are to 280 mg and then to 140 mg for second and third recurrences; treatment should be discontinued for a fourth recurrence.

Coadministration of ibrutinib with a strong (eg, boceprevir [Victrelis], clarithromycin, cobicistat, conivaptan [Vaprisol], posaconazole, voriconazole) or moderate (eg, aprepitant, cimetidine, ciprofloxacin, clotrimazole) CYP3A inhibitor can increase ibrutinib plasma concentrations, potentially increasing the likelihood of adverse reactions. For concomitant use with a moderate CYP3A inhibitor, the ibrutinib dose should be modified based on adverse reactions. 

Coadministration with posaconazole at doses higher than those specified below or other strong CYP3A inhibitors should be avoided. The ibrutinib dose should be reduced to 280 mg once daily for concurrent use with posaconazole immediate-release tablet 200 mg twice daily, posaconazole delayed-release tablet 300 mg once daily, or voriconazole at any dose. The ibrutinib dose should also be modified based on adverse reactions. If higher-dose posiconazole or other strong CYP3A inhibitors are to be used for a short period (eg, as anti-infectives for ≤ 7 days), ibrutinib should be interrupted for the duration of such treatment.

For patients with mild liver impairment (Child-Pugh class A), the recommended ibrutinib dose is 140 mg daily. Ibrutinib should be avoided in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C).

Safety Profile

In the open-label study in 42 patients, the most common adverse events of any grade were fatigue (57%), bruising (40%), diarrhea (36%), stomatitis (29%), muscle spasms (29%), nausea (26), and hemorrhage (26%); the most common grade 3 or 4 events included fatigue (12%), pneumonia (10%), sepsis (10%), and diarrhea (10%). Grade 3 atrial fibrillation occurred in one patient (2%). The most common lab abnormalities of any grade/grade 3 or 4 were thrombocytopenia (33%/0%), neutropenia (10%/10%), and anemia (24%/2%). Adverse events led to dose reduction in 26% of patients and to permanent treatment discontinuation in 24%, with the most common causes of treatment discontinuation being fatigue and pneumonia.

Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, atrial fibrillation, hypertension, second primary malignancies (including skin cancers and other carcinomas), tumor-lysis syndrome, and embryofetal toxicity. Patients must be monitored for bleeding, fever and infection, blood pressure, and atrial fibrillation. Complete blood cell counts should be monitored monthly. Women must be advised of the potential risk to a fetus and to avoid pregnancy while taking the drug and for 1 month after stopping treatment. Men must be advised to avoid fathering a child during the same period. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA expands ibrutinib indications to chronic GVHD. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569711.htm. Accessed November 8, 2017.

2. Imbruvica (ibrutinib) capsules prescribing information, Pharmacyclics LLC, Janssen Biotech, Inc, August 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205552s017lbl.pdf. Accessed November 8, 2017.