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Imbruvica

Generic Name: Ibrutinib
Class: Antineoplastic Agents
Chemical Name: 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one
Molecular Formula: C25H24N6O2
CAS Number: 936563-96-1

Medically reviewed on Oct 8, 2018

Introduction

Antineoplastic agent; inhibitor of Bruton's tyrosine kinase (BTK).1 4 5 6 7

Uses for Imbruvica

Mantle Cell Lymphoma

Treatment of mantle cell lymphoma in patients who have received at least one prior therapy; designated an orphan drug by FDA for this use.1 9

Current indication based on overall response rate; improvement in patient-reported outcomes and overall survival not established.1

Continued FDA approval for this indication may be contingent on confirmation of clinical benefit in additional trials.1

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Used alone or in combination with bendamustine and rituximab for the treatment of CLL and SLL, including CLL/SLL harboring the 17p13.1 deletion (17p deletion) chromosomal abnormality; designated an orphan drug by FDA for this use.1 3 9 16 23 25

Marginal-zone Lymphoma

Treatment of marginal-zone lymphoma in patients who have received at least one prior anti-CD20-based therapy;1 24 designated an orphan drug by FDA for this use.9

Current indication based on favorable overall response rate; clinical benefit not established.1 Continued FDA approval for this indication may be contingent on confirmation of clinical benefit in additional trials.1

Waldenstrom Macroglobulinemia

Treatment of Waldenstrom macroglobulinemia; designated an orphan drug by FDA for this use.1 9 15 19

Chronic Graft-versus-host Disease (GVHD)

Treatment of chronic GVHD following failure of at least one prior systemic therapy;1 designated an orphan drug by FDA for this use.9

Imbruvica Dosage and Administration

Administration

Oral Administration

Administer orally once daily at approximately the same time each day.1

Swallow capsules whole with water; do not open, break, or chew.1

Swallow tablets whole with water; do not cut, crush, or chew.1

Dosage

Adults

Mantle Cell Lymphoma
Oral

560 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 2

CLL/SLL
Oral

420 mg once daily (as a single agent or in combination with bendamustine and rituximab).1 Continue therapy until disease progression or unacceptable toxicity occurs.1

In the HELIOS study, patients received ibrutinib (420 mg once daily) continuously, bendamustine (70 mg/m2 IV over 30 minutes) on days 2 and 3 of cycle 1 and on days 1 and 2 of cycles 2–6, and rituximab 375 mg/m2 by IV infusion on day 1 of cycle 1 followed by 500 mg/m2 on day 1 of cycles 2–6.1 25 Continue ibrutinib therapy until disease progression or unacceptable toxicity occurs.1 Repeat treatment cycles every 28 days.1 25

Marginal-zone Lymphoma
Oral

560 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Waldenstrom Macroglobulinemia
Oral

420 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1 19

Dosage adjustment not necessary in patients undergoing plasmapheresis.1

Chronic GVHD
Oral

420 mg once daily.1 Continue therapy until progression of chronic GVHD, recurrence of underlying malignancy, or unacceptable toxicity.1 Discontinue therapy when treatment for chronic GVHD is no longer necessary.1

Dosage Modification for Toxicity

If ≥ grade 3 nonhematologic toxicity, ≥ grade 3 neutropenia with infection or fever, or grade 4 hematologic toxicity occurs, interrupt therapy.1 Following recovery from toxicity (i.e., return to baseline or resolution to grade 1), resume (or discontinue) therapy as described in Table 1.1

Table 1: Dosage Modifications for Ibrutinib Toxicity

Dosage Modification after Recovery from Toxicity

Toxicity Occurrence

Mantle Cell Lymphoma or Marginal-zone Lymphoma (Starting Dosage = 560 mg daily)

CLL/SLL, Waldenstrom Macroglobulinemia, or Chronic GVHD (Starting Dosage = 420 mg daily)

First

Restart at 560 mg daily

Restart at 420 mg daily

Second

Restart at 420 mg daily

Restart at 280 mg daily

Third

Restart at 280 mg daily

Restart at 140 mg daily

Fourth

Discontinue ibrutinib

Discontinue ibrutinib

Dosage Modification with Concomitant Drugs or Foods Affecting Hepatic Microsomal Enzymes

Avoid concomitant use with potent CYP3A inhibitors; if short-term (≤7 days) therapy with a potent CYP3A inhibitor is necessary, withhold ibrutinib during such therapy.1 If concomitant use with posaconazole or voriconazole cannot be avoided, reduce ibrutinib dosage.1 Ibrutinib dosage reduction also required if used concomitantly with a moderate CYP3A inhibitor.1 (See Interactions.)

Special Populations

Hepatic Impairment

Mild (Child-Pugh class A) hepatic impairment: Reduce dosage to 140 mg once daily.1 Closely monitor for signs of toxicity.1 (See Hepatic Impairment under Cautions.)

Moderate (Child-Pugh class B) hepatic impairment: Reduce dosage to 70 mg once daily.1 Closely monitor for signs of toxicity.1

Severe (Child-Pugh class C) hepatic impairment: Avoid use.1

Renal Impairment

No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time; however, certain ibrutinib toxicities may be more frequent in geriatric patients.1 (See Geriatric Use under Cautions.)

Cautions for Imbruvica

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hemorrhage

Hemorrhagic events, sometimes fatal, observed.1 2 3 11 16 Serious (grade 3 or higher) bleeding events, including intracranial hemorrhage, subdural hematoma, GI bleeding, hematuria, and postprocedural hemorrhage, observed.1 2 3 11 16

Increased risk of hemorrhagic events with concomitant use of ibrutinib and antiplatelet or anticoagulant therapies; monitor for manifestations of bleeding.1

Consider potential benefits and risks of withholding ibrutinib therapy for at least 3–7 days prior to and following surgery.1

Infectious Complications

Serious infections (bacterial, viral, or fungal), sometimes fatal, observed.1 16

Progressive leukoencephalopathy (PML) and Pneumocystis jirovecii (formerly P. carinii) pneumonia also observed.1

Monitor for signs and symptoms of infection and initiate appropriate anti-infective treatment as clinically indicated.1 Consider prophylaxis according to current standard of care in patients at high risk for opportunistic infections.1

Myelosuppression

Cytopenias, including thrombocytopenia, anemia, and neutropenia, observed.1 Serious (grade 3 or 4) cytopenias observed in patients with B-cell malignancies receiving single-agent ibrutinib.1

Monitor CBC counts monthly.1 If myelosuppression occurs, reduce dosage or interrupt therapy.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Cardiac Effects

Serious arrhythmias, sometimes fatal, observed.1 16 Serious (grade 3 or higher) ventricular tachyarrhythmias, atrial fibrillation, and atrial flutter observed.1

Increased risk of arrhythmia in patients with cardiac risk factors, hypertension, acute infections, or history of arrhythmias.1 16

Hypertension also reported.1

Monitor for development of arrhythmia, new-onset hypertension, or hypertension not adequately controlled with medical management.1

If symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, angina) or new-onset dyspnea occur, monitor ECG and manage as clinically indicated.1 If arrhythmia persists, consider reducing dosage and carefully weigh potential benefit of drug against risks of continued therapy.1

If hypertension occurs, initiate or adjust antihypertensive therapy as clinically indicated.1

Development of Second Primary Malignancy

Development of other malignancies, including non-skin carcinomas, reported in 5–14% of ibrutinib-treated patients.1 Non-melanoma skin cancer occurred in 4–11% of ibrutinib-treated patients.1

Tumor Lysis Syndrome

Tumor lysis syndrome reported infrequently.1

Assess risk of developing tumor lysis syndrome at baseline and take appropriate precautions.1 Closely monitor patients and treat as clinically indicated.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity demonstrated in animals.1 Avoid pregnancy during therapy and for 1 month after discontinuance of drug.1 (See Advice to Patients.) If used during pregnancy or if patient becomes pregnant while receiving drug, apprise patient of potential fetal hazard.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

In women of childbearing potential, manufacturer recommends a pregnancy test prior to initiating ibrutinib therapy.1

Lactation

Not known whether ibrutinib or its metabolites are distributed into human milk or if drug has any effect on milk production or nursing infant.1

Consider benefits of breast-feeding and importance of ibrutinib to the woman along with the potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In clinical trials, no difference in efficacy in geriatric patients (≥65 years of age) compared with younger adults, but toxicity (i.e., anemia, grade 3 or higher pneumonia) occurred more frequently in geriatric patients.1

Hepatic Impairment

Safety not established.1

Increased systemic exposure and peak plasma concentrations in patients with mild to severe hepatic impairment.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Adjust dosage as appropriate and monitor for toxicity if used in patients with mild hepatic impairment.1 (See Special Populations under Dosage and Administration.)

Avoid use in patients with moderate or severe hepatic impairment.1

Renal Impairment

Systemic exposure apparently not affected in patients with Clcr >25 mL/minute.1

No experience in patients with severe renal impairment (Clcr <25 mL/minute) or in those undergoing dialysis.1

Common Adverse Effects

Previously treated mantle cell lymphoma: Thrombocytopenia,1 diarrhea,1 2 neutropenia,1 anemia,1 fatigue,1 2 musculoskeletal pain,1 peripheral edema,1 2 upper respiratory tract infection,1 2 nausea,1 2 bruising,1 dyspnea,1 2 constipation,1 2 rash,1 abdominal pain,1 vomiting,1 2 decreased appetite.1 2

CLL/SLL: Thrombocytopenia,1 16 25 neutropenia,1 16 25 diarrhea,1 16 23 25 anemia,1 16 25 fatigue,1 16 23 25 musculoskeletal pain,1 upper respiratory tract infection,1 rash,1 nausea,1 16 23 25 bruising,1 pyrexia,1 16 25 hemorrhage,1 25 cough.1

Marginal-zone lymphoma: Thrombocytopenia,1 24 fatigue,1 24 anemia,1 24 diarrhea,1 24 bruising,1 musculoskeletal pain,1 hemorrhage,1 rash,1 nausea,1 24 arthralgia,1 24 peripheral edema,1 24 cough,1 24 neutropenia,1 dyspnea,1 24 upper respiratory tract infection.1 24

Waldenstrom macroglobulinemia: Neutropenia,1 thrombocytopenia,1 diarrhea,1 rash,1 nausea,1 muscle spasms,1 fatigue.1

Chronic GVHD: Fatigue,1 bruising,1 diarrhea,1 thrombocytopenia,1 muscle spasms,1 stomatitis,1 hemorrhage,1 nausea,1 anemia,1 pneumonia.1

Other clinically important adverse effects include diarrhea and visual disturbances (i.e., blurry vision, decreased visual acuity).1

Interactions for Imbruvica

Principally metabolized by CYP3A and, to a lesser extent, by CYP2D6 to an active dihydrodiol metabolite (PCI-45227).1

Ibrutinib and PCI-45227 are not expected to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce CYP isoenzymes 1A2, 2B6, or 3A at clinically relevant concentrations in vitro.1

Ibrutinib not a substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro; may inhibit P-gp and BCRP transport at clinically relevant concentrations.1

CYP3A Inhibitors

Possible pharmacokinetic interaction (increased serum ibrutinib concentrations) and increased incidence of drug toxicity.1 Moderate CYP3A inhibitors may increase AUC and peak plasma concentrations of ibrutinib by approximately threefold.1 Larger increases in AUC and peak plasma concentrations (e.g., by 24- and 29-fold, respectively) possible with potent CYP3A inhibitors; however, less substantial increases in AUC expected with voriconazole (e.g., by approximately 5.7-fold) and posaconazole (e.g., by threefold to tenfold).1 (See Specific Drugs and Foods under Interactions.)

Avoid concomitant use with potent CYP3A inhibitors.1 If short-term (≤7 days) administration of a potent CYP3A inhibitor is required, withhold ibrutinib during such administration.1 If concomitant use with posaconazole or voriconazole cannot be avoided, reduce ibrutinib dosage.1 (See Specific Drugs and Foods under Interactions.)

If concomitant use with a moderate CYP3A inhibitor is necessary, reduce ibrutinib dosage to 140 mg once daily in patients with mantle cell lymphoma, marginal-zone lymphoma, CLL/SLL, or Waldenstrom macroglobulinemia, and to 420 mg once daily in patients with chronic GVHD.1 14 If the moderate CYP3A inhibitor is discontinued, resume ibrutinib therapy at the dosage used prior to initiation of the moderate CYP3A inhibitor.1

Closely monitor patient for adverse effects if concomitant use of a CYP3A inhibitor cannot be avoided, and interrupt or reduce ibrutinib dosage accordingly.1

CYP3A Inducers

Possible pharmacokinetic interaction (decreased serum ibrutinib concentrations).1 Potent inducers of CYP3A may reduce peak plasma concentration and AUC of ibrutinib by >10-fold.1 Moderate CYP3A inducers may reduce ibrutinib AUC by up to threefold.1

Avoid concomitant use with potent CYP3A inducers.1 (See Specific Drugs and Foods under Interactions.)

Substrates of Efflux Transport Systems

Possible pharmacokinetic interaction (increased plasma P-gp or BCRP substrate concentrations).1 (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticoagulants

Increased risk of hemorrhagic events1

Monitor for bleeding manifestations1

Antifungals, azole (e.g., ketoconazole, posaconazole, voriconazole)

Possibly increased peak plasma concentration and systemic exposure of ibrutinib1

Ketoconazole: Increased ibrutinib peak plasma concentration and AUC by 29- and 24-fold, respectively1 26

Voriconazole: Increased ibrutinib peak plasma concentration and AUC by 6.7- and 5.7-fold, respectively1

Posaconazole: Simulations suggest increased ibrutinib AUC by 3-fold to 10-fold1

Potent CYP3A Inhibitor: Avoid concomitant use if possible1

If concomitant use cannot be avoided, closely monitor patient for adverse effects and interrupt or reduce ibrutinib dosage accordingly1

Moderate CYP3A inhibitor: If concomitant use is required, reduce ibrutinib dosage to 140 mg once daily in patients with B-cell malignancies (mantle cell lymphoma, marginal-zone lymphoma, CLL/SLL, Waldenstrom macroglobulinemia), and to 420 mg once daily in patients with chronic GVHD1

Potent CYP3A inhibitor (except for posaconazole and voriconazole): If concomitant use of the CYP3A inhibitor is short term (≤7 days), withhold ibrutinib therapy during administration of the CYP3A inhibitor1

Posaconazole oral suspension 100 mg once or twice daily or 200 mg twice daily or voriconazole 200 mg twice daily: Reduce ibrutinib dosage to 140 mg once daily in patients with B-cell malignancies (mantle cell lymphoma, marginal-zone lymphoma, CLL/SLL, Waldenstrom macroglobulinemia)1 14 and to 280 mg once daily in patients with chronic GVHD1

Posaconazole oral suspension 200 mg 3 times daily or 400 mg twice daily, posaconazole IV 300 mg once daily, or posaconazole delayed-release tablets 300 mg once daily: Reduce ibrutinib dosage to 70 mg once daily in patients with B-cell malignancies (mantle cell lymphoma, marginal-zone lymphoma, CLL/SLL, or Waldenstrom macroglobulinemia)1 and to 140 mg once daily in patients with chronic GVHD1

If concomitant use of a CYP3A inhibitor is discontinued, resume ibrutinib therapy at the dosage used prior to initiation of the CYP3A inhibitor1

Antimycobacterials, rifamycins (e.g., rifampin)

Rifampin, a potent CYP3A inducer, decreased ibrutinib peak plasma concentration and AUC by 13- and 10-fold, respectively1 26

Moderate CYP3A inducers: Possibly decreased AUC of ibrutinib by up to threefold1

Avoid concomitant use with potent CYP3A inducers1

Antiplatelet agents

Increased risk of hemorrhagic events1

Monitor for bleeding manifestations1

Antiretroviral agents, nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz)

Potent CYP3A inducers: Possibly decreased peak plasma concentration and AUC of ibrutinib by >10-fold1

Moderate CYP3A inducers: Possibly decreased AUC of ibrutinib by up to threefold1

Avoid concomitant use with potent CYP3A inducers1

Digoxin

Concentrations of oral drugs that are substrates of P-gp or BCRP and have a narrow therapeutic index may be increased1

Grapefruit or grapefruit juice

Grapefruit products are moderate to potent inhibitors of CYP3A; possibly increased ibrutinib concentrations1

Avoid concomitant use

Macrolides (erythromycin)

Erythromycin, a moderate CYP3A inhibitor, increased ibrutinib peak plasma concentration and AUC by 3.4- and 3-fold, respectively1

Erythromycin: If concomitant use cannot be avoided, reduce ibrutinib dosage to 140 mg once daily in patients with B-cell malignancies (mantle cell lymphoma, marginal-zone lymphoma, CLL/SLL, Waldenstrom macroglobulinemia) and to 420 mg once daily in patients with chronic GVHD1 14

If concomitant erythromycin is discontinued, resume ibrutinib therapy at the dosage used prior to initiation of erythromycin1

Methotrexate

Concentrations of oral drugs that are substrates of P-gp or BCRP and have a narrow therapeutic index may be increased1

Seville oranges or Seville orange juice

Seville orange products are moderate to potent inhibitors of CYP3A; possibly increased ibrutinib concentrations1

Avoid concomitant use

Imbruvica Pharmacokinetics

Absorption

Food

Following oral administration in healthy individuals in a fasted condition, absolute bioavailability is 2.9%.1

Systemic exposure increases with doses up to 840 mg in patients with B-cell malignancies.1

Following repeated doses of 420 or 560 mg daily, steady-state concentrations achieved in 1 week with accumulation ratio of 1–1.6.1

Oral administration with high-fat, high-calorie meal (800–1000 calories with approximately 50% of calories from fat) increases peak plasma concentration by twofold to fourfold and systemic exposure by twofold, compared with administration following overnight fasting.1

Special Populations

Patients with mild hepatic impairment (Child-Pugh class A): Peak plasma concentration or systemic exposure increased by 5.2- or 2.7-fold, respectively.1

Patients with moderate hepatic impairment (Child-Pugh class B): Peak plasma concentration or systemic exposure increased by 8.8- or 8.2-fold, respectively.1

Patients with severe hepatic impairment (Child-Pugh class C): Peak plasma concentration or systemic exposure increased by 7- or 9.8-fold, respectively.1

Systemic exposure apparently not affected in patients with Clcr >25 mL/minute.1

Distribution

Extent

Extensive tissue distribution; not known whether distributed into milk.1

Plasma Protein Binding

97.3%.1

Elimination

Metabolism

Metabolized principally by CYP3A and, to a lesser extent, by CYP2D6 to the active dihydrodiol metabolite PCI-45227.1

Elimination Route

Eliminated in feces (80%) and urine (<10%).1

Half-life

4–6 hours.1

Special Populations

Age and gender do not substantially affect pharmacokinetics of ibrutinib.1

Stability

Storage

Oral

Capsules and Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Selectively and irreversibly inhibits BTK, resulting in inhibition of downstream effector activity within the B-cell antigen receptor (BCR) signaling pathway.1 4 5 6 7

  • Inhibits other receptor kinases (e.g., Bmx/Etk, EGFR, Hck, Yes) in vitro.8

  • Inhibits proliferation and survival of malignant B-cells in vivo.1

  • Demonstrates cell migration and substrate adhesion of CLL cells and mantle cell lymphoma cells in vitro;1 2 mobilization of cells from tissues to peripheral blood results in a transient increase in absolute lymphocyte count in peripheral blood.2 12 13

  • Demonstrates substantial activity in activated B-cell-like diffuse B-cell non-Hodgkin's lymphoma (ABC-DLBCL) cells expressing wild-type caspase recruitment domain-containing protein-11 (wild-type CARD-11) in vitro and in vivo.5 6

Advice to Patients

  • Importance of advising patients to take ibrutinib as directed by their clinician and at approximately the same time each day.1 If a dose is missed, importance of administering the missed dose on the same day as soon as it is remembered.1 Patients should be advised not to take 2 doses on the same day to make up for a missed dose.1

  • Importance of advising patients to take ibrutinib capsules or tablets orally with a glass of water; do not open, break, or chew capsules or cut, crush, or chew tablets.1

  • Risk of bleeding.1 Importance of promptly informing clinician of any episodes of unusual bleeding (e.g., severe headache, blood in stool or urine, prolonged or uncontrolled bleeding).1 Importance of notifying clinician before any planned surgeries, including dental procedures.1

  • Risk of serious infection.1 Importance of reporting signs or symptoms of possible infection (e.g., chills, fever).1

  • Risk of arrhythmia.1 Importance of informing clinician if palpitations, lightheadedness, dizziness, fainting, shortness of breath, or chest discomfort occurs.1

  • Risk of hypertension; may require antihypertensive therapy.1

  • Possible risk of developing a second primary malignancy (e.g., skin cancer).1

  • Risk of tumor lysis syndrome.1 Importance of reporting signs or symptoms of tumor lysis syndrome (e.g., arrhythmia, seizure).1

  • Risk of fetal harm.1 Apprise patient of potential hazard to the fetus if used during pregnancy.1 Women of childbearing potential should avoid becoming pregnant during therapy and for ≥1 month after discontinuance of therapy; men should also avoid fathering a child during therapy and for ≥1 month after discontinuance of therapy.1

  • Risk of diarrhea.1 Importance of advising patients to maintain adequate hydration during ibrutinib therapy.1 Importance of informing clinician if diarrhea persists.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 Importance of advising patients not to consume grapefruit or Seville oranges.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ibrutinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

70 mg

Imbruvica

Pharmacyclics (comarketed by Janssen Biotech)

140 mg

Imbruvica

Pharmacyclics (comarketed by Janssen Biotech)

Tablets

140 mg

Imbruvica

Pharmacyclics (comarketed by Janssen Biotech)

280 mg

Imbruvica

Pharmacyclics (comarketed by Janssen Biotech)

420 mg

Imbruvica

Pharmacyclics (comarketed by Janssen Biotech)

560 mg

Imbruvica

Pharmacyclics (comarketed by Janssen Biotech)

AHFS DI Essentials™. © Copyright 2018, Selected Revisions October 8, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Pharmacyclics, Inc. and Janssen Biotech, Inc. Imbruvica (ibrutinib) capsules and tablets, for oral use prescribing information. Sunnyvale, CA; 2018 Feb.

2. Wang ML, Rule S, Martin P et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013; 369:507-16. http://www.ncbi.nlm.nih.gov/pubmed/23782157?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4513941&blobtype=pdf

3. Byrd JC, Furman RR, Coutre SE et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369:32-42. http://www.ncbi.nlm.nih.gov/pubmed/23782158?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3772525&blobtype=pdf

4. Advani RH, Buggy JJ, Sharman JP et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013; 31:88-94. http://www.ncbi.nlm.nih.gov/pubmed/23045577?dopt=AbstractPlus

5. Dasmahapatra G, Patel H, Dent P et al. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol. 2013; 161:43-56. http://www.ncbi.nlm.nih.gov/pubmed/23360303?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3739300&blobtype=pdf

6. Chavez JC, Sahakian E, Pinilla-Ibarz J. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia. Core Evid. 2013; 8:37-45. http://www.ncbi.nlm.nih.gov/pubmed/23717217?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3662532&blobtype=pdf

7. Dias AL, Jain D. Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton's Tyrosine Kinase Inhibition. Cardiovasc Hematol Agents Med Chem. 2013; 11:265-71. http://www.ncbi.nlm.nih.gov/pubmed/24433470?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4010045&blobtype=pdf

8. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205552Orig1s000: Pharmacology review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000PharmR.pdf

9. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 May 21. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

10. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012; 120:1175-84. http://www.ncbi.nlm.nih.gov/pubmed/22715122?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3418714&blobtype=pdf

11. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205552Orig1s000: Summary review. From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000SumR.pdf

12. Rossi D, Gaidano G. Lymphocytosis and ibrutinib treatment of CLL. Blood. 2014; 123:1772-4. http://www.ncbi.nlm.nih.gov/pubmed/24652958?dopt=AbstractPlus

13. Herman SE, Niemann CU, Farooqui M et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014; :. http://www.ncbi.nlm.nih.gov/pubmed/24699307?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4185271&blobtype=pdf

14. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 205552Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000ClinPharmR.pdf

15. Pharmacyclics, Sunnyvale, CA: Personal communication.

16. Byrd JC, Brown JR, O'Brien S et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014; 371:213-23. http://www.ncbi.nlm.nih.gov/pubmed/24881631?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4134521&blobtype=pdf

17. Farooqui MZ, Valdez J, Martyr S et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb; 16:169-76.

18. Byrd JC, Furman RR, Coutre S et al. The bruton's tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naive (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: New and updated results of 116 patients in a phase Ib/II study. Blood. 2012; 120(21):189. Abstract.

19. Treon SP, Tripsas CK, Meid K et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015; 372:1430-40.

20. Farooqui M, Aue G, Valdez J et al. Single agent ibrutinib (PCI-32765) achieves equally good and durable responses in chronic lymphocytic leukemia (CLL) patients with and without deletion 17p. Oral presentation at the 55th Annual Meeting of the American Society of Hematology, New Orleans, LA, 2012 Dec 7-10.

21. Wiestner A, Farooqui M, Valdez J, et al. Single agent ibrutinib (PCI-32765) is highly effective in chronic lymphocytic leukaemia patients with 17p deletion. Hematol Oncol. 2013; 31:96-150. http://www.ncbi.nlm.nih.gov/pubmed/22961993?dopt=AbstractPlus

22. O'Brien SM, Furman RR, Coutre SE et al. Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p disease. J Clin Oncol. 2014; 32:5s (American Society of Clinical Oncology Annual Meeting Abstracts):Abstract No. 7014.

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24. Noy A, de Vos S, Thieblemont C et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017; 129:2224-2232. http://www.ncbi.nlm.nih.gov/pubmed/28167659?dopt=AbstractPlus

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