Ibrutinib: BTK inhibitor offers hope to patients with B-cell malignancies

Ibrutinib is an anticancer treatment that targets B-cell malignancies.

In November, the FDA approved ibrutinib (Imbruvica; Pharmacyclics and Janssen) for the treatment of patients with mantle cell lymphoma. Studies are underway to evaluate its potential in chronic lymphocytic leukemia, multiple myeloma and diffuse large B-cell lymphoma.

Mechanism of action

The B-cell antigen receptor (BCR) pathway controls normal B-cell differentiation and function. Abnormal activity can lead to development of B-cell lymphoid malignancies. Bruton’s tyrosine kinase (BTK) is one of the critical enzymes in the BCR pathway, and aberrant activity of BTK has been implicated in the development of B-cell malignancies.

Ibrutinib is a small-molecule irreversible inhibitor of BTK and, thereby, inhibits the abnormal BCR signaling.

Dose-ranging studies showed there was >95% blocking of BTK sites at ibrutinib doses as low as 2.5 mg/kg per day. Larger doses did not result in greater BTK site occupancy. The dose of ibrutinib was based on optimal biologic dosing instead of maximally tolerated dose.

Mantle cell lymphoma

Wang and colleagues conducted a non-comparative trial to study the use of ibrutinib in 111 patients (median age, 68 years) with relapsed or refractory mantle cell lymphoma. Patients were separated into two cohorts: those who had at least two cycles of bortezomib (Velcade, Millennium Pharmaceuticals) and those who had not.

Ibrutinib was dosed at 560 mg orally daily. Overall response rate served as the primary endpoint. Most patients were male and had intermediate or high-risk disease. Patients had undergone a median three prior therapies.

The ORR was 68% (47% partial response and 21% complete response.) Researchers observed comparable response rates in the two cohorts.

Among patients who had a response, the median duration of response was 17.5 months. Table 1 provides an overview of reported adverse effects.

CLL/SLL

Byrd and colleagues enrolled 85 patients (median age, 66 years) with refractory or relapsed CLL or small lymphocytic lymphoma (SLL) in an open-label, noncomparative study. These patients received ibrutinib 420 mg or 840 mg orally daily.

Most of the patients were male and had Rai stage III/IV disease. Patients had undergone a median four previous therapies.

The ORR was 71% in both dose cohorts. The response rate was similar among all patients with different prognostic features, except for those with mutated immunoglobulin variable-region heavy-chain genes.

There was a period of lymphocytosis noted in 78% of patients that peaked at about 4 weeks of treatment and then resolved. The adverse effects reported in this trial are described in Table 1.

O’Brien and colleagues studied ibrutinib as initial treatment in older patients with CLL/SLL. All patients were aged 65 years or older (median age, 71 years).

Researchers initially randomly assigned patients to receive ibrutinib 420 mg or 840 mg daily, but the higher-dose arm was discontinued because of similar response rates.

Frequency and severity of adverse effects served as the primary endpoint. Adverse effects are included in Table 1.

The ORR was 71% (13% complete response, 3% modular partial response, 55% partial response). The researchers concluded that ibrutinib was well tolerated in this patient population.

Pharmacokinetics

Ibrutinib exhibits rapid oral absorption, with a half-life of about 4 to 6 hours. It is hepatically metabolized primarily via the CYP3A4/5 enzymes, with a minor involvement of CYP2D6. There is only minimal renal excretion.

The use of ibrutinib has not been studied in patients with hepatic impairment (those with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal), although it is expected that the excretion of ibrutinib in these patients would be reduced.

Older patients had a 30% higher area under the curve (AUC) than younger patients, and those assigned ibrutinib with a high-fat meal had about a twofold increase in AUC. However, neither of these situations led to increased toxicities.

Dosing

Ibrutinib is FDA approved for treatment of mantle cell lymphoma at a dose of 560 mg orally daily. The capsules are available as 140 mg each.

The dosage should be swallowed whole with a full glass of water. There are dose modifications available for patients who experience grade ≥3 nonhematologic adverse effects, or neutropenia with fever or infection, as well as for grade 4 hematologic adverse effects. Patients should be advised to avoid grapefruit and grapefruit juice.

Drug interactions

Concomitant treatment with ibrutinib and strong inhibitors and inducers of CYP3A4/5 and CYP2D6 should be avoided. There are no dosing modifications recommended to manage these interactions.

If patients must be treated with a short course of a strong CYP3A4 inhibitor (eg, voriconazole), then it is recommended to temporarily hold the ibrutinib. If concomitant therapy with a moderate CYP3A4 inhibitor (eg, fluconazole or ciprofloxacin) is necessary, then it is recommended that the dose of ibrutinib be reduced to 140 mg orally daily.

Adverse effects

Ibrutinib is fairly well tolerated. The most common adverse effects (see Table 1) reported with ibrutinib are diarrhea, nausea and fatigue, and they most often are grade 1 or grade 2. The most common grade 3 or grade 4 toxicities are diarrhea, neutropenia and thrombocytopenia.

Conclusion

Ibrutinib is a promising new agent with a novel mechanism of action. The adverse effects are usually mild and manageable. There are ongoing trials studying the use of ibrutinib alone and combined with monoclonal antibodies and other antineoplastic agents.

— Lisa K. Lohr, PharmD, BCPS, BCOP, is a clinical pharmacy specialist and oncology medication therapy management provider at the University of Minnesota Physicians Cancer Care at Fairview in Minneapolis. She also is a HemOnc Today Editorial Board member. She may be reached at the University of Minnesota Physicians Cancer Care at Fairview, 424 Harvard St. SE (MMC 114), Minneapolis, MN 55455.

Disclosure: Lohr reports no relevant financial disclosures.

 

 Table 1. Adverse effects reported with ibrutinib.

Adverse effect (incidence >15%)	All grades	Grades 3-5
Diarrhea	49%-68%	2%-13%
Nausea	18%-48%	0%-1%
Fatigue	32%-41%	3%-5%
Upper respiratory infection/urinary tract infection/sinusitis	13%-33%	0%-5%
Cough	18%-31%	0%
Peripheral edema	21%-29%	0%-1%
Hypertension	18%-29%	5%-6%
Pyrexia	18%-28%	1%-5%
Dyspnea	27%	5%
Rash	13%-27%	0%-2%
Arthralgia	23%-27%	0%
Dizziness	18%-26%	1-3%
Dyspepsia/gastroesophageal reflux disease	19%-26%	0%
Constipation	18%-25%	0%-1%
Vomiting	16%-23%	0%-1%
Decreased appetite	21%	2%
Muscle spasms	13%-20%	0%-1%
Abdominal pain	17%-19%	0%-5%
Hemolytic anemia	18%-19%	1%-3%
Neutropenia	15%-18%	15%-16%
Thrombocytopenia	13%-18%	3%-11%
Contusion	16%-17%	0%
Anemia	16%	0%
Anxiety	16%	0%
Epistaxis	16%	0%
Insomnia	16%	0%
Petechiae	16%	0%
Stomatitis	16%	0%

References:

• Akinleye A. J Hematol Oncol. 2013;6:59-67.
• Bhatt V. Pharmacotherapy. 2013;doi:10.1022/phar.1366.
• Byrd JC. N Engl J Med. 2013;369:32-42.
• O’Brien S. Lancet Oncol. 2014;15:48-58.
• Wang ML. N Engl J Med. 2013;369:507-516.