Ibrutinib in the Management of B-cell Malignancies

The Journal of Targeted Therapies in CancerApril 2015
Volume 4
Issue 2

While ibrutinib is a relatively new option in the treatment of B-cell NHL, it has convincing antitumor activity as a single agent in a wide variety of B-cell lymphoma subtypes and is a viable therapeutic option for patients.

Michelle A. Fanale, MD

Michelle A. Fanale, MD

Amanda Przespolewski, DO

Clinical Instructor of Medicine

Department of Medicine

Roswell Park Cancer Institute

State University of New York at Buffalo

Eugene R. Przespolewski, PharmD

Eugene R. Przespolewski, PharmD

Eugene R. Przespolewski, PharmD

Oncology Pharmacist

Department of Pharmaceutical Services, Adjunct Professor of University, Buffalo School of Pharmacy and Pharmaceutical Sciences, Erie County Medical Center, Buffalo, NY

Francisco J. Hernandez-Ilizaliturri, MD

Francisco J. Hernandez-Ilizaliturri, MD

Francisco J. Hernandez-Ilizaliturri, MD

Associate Professor of Medicine, Department of Medicine, Assistant Professor of Immunology, Department of Immunology, Roswell Park Cancer Institute

Buffalo, NY


Bruton’s tyrosine kinase (BTK) is a crucial component of the B-cell receptor-signaling pathway that has been associated with the pathogenesis of B-cell malignancies. Ibrutinib is an oral BTK inhibitor that showed promising antitumor activity in preclinical lymphoma models. Subsequently, ibrutinib was tested in prospective clinical studies and was found to be active in various B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia (WM).

In addition, ibrutinib appears to be well tolerated in patients with lymphoma/leukemia. Ongoing clinical studies are incorporating this novel agent in the management of other subtypes of B-cell lymphoid malignancies and testing the drug’s antitumor activity as a single agent or in combination with other agents in patients with CLL/MCL or WM.


Non-Hodgkin’s lymphoma (NHL) is a diverse group of malignancies that exhibit distinct biology, clinical behavior, and outcomes. It is the sixth-most diagnosed cancer in the United States. NHL accounts for 4% to 5% of the cancer cases and 3% to 4% of all cancer-related deaths. B-cell lymphoma constitutes a large majority of NHL seen in the United States and includes subtypes such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Waldenström’s macroglobulinemia (WM). These subtypes of NHL have been treated with traditional intravenous systemic chemotherapy with or without monoclonal antibodies (mAbs) targeting CD20 with varying degrees of efficacy. The early use of rituximab as a single agent or in combination with various systemic chemotherapy regimens (ie, CVP [cyclophosphamide, vincristine, prednisone], CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], fludarabine) has resulted in improved response rates, duration of remission, and improved overall survival (OS) in patients with follicular lymphoma (FL) and with DLBCL.2-10

Two recently published retrospective analyses suggest that the use of mAbs targeting CD20 (rituximab) in combination with systemic polychemotherapy improves the OS in patients with FL when compared with chemotherapy alone.11,12On the other hand, a significant number of patients with certain subtypes of B-cell lymphoma relapsed after initial response or failed to achieve a durable remission, indicating the need for drug discovery. Moreover, elderly patients or those with significant comorbid conditions may require alternative effective and less toxic regimens (ie, nonchemotherapy regimens).


Ibrutinib (PCI-32765) is a novel, oral, targeted agent that inhibits Bruton’s tyrosine kinase (BTK), suppressing the B-cell receptor (BCR) signaling pathway with proven activity in certain subtypes of NHL. It is emerging as a therapeutic option for patients with a variety of B-cell lymphoma because of its clinical activity, tolerability, and easy administration. The US Food and Drug Administration (FDA) has approved ibrutinib for the treatment of patients with relapsed/refractory CLL or MCL and for patients with previously untreated CLL (p53 deletion) and WM.Ibrutinib forms a covalent bond with cysteine 481 on the BTK enzyme and inhibits BTK activity at Tyr-223.13-16Ibrutinib’s empiric formula is C25H24N6O2 and its molecular weight is 440.50.16

Pharmacokinetics and Pharmacodynamics

Bruton’s tyrosine kinase is a Tec family kinase that is involved in the BCR signaling pathway.15The BCR pathway and BTK are implicated in NHL pathogenesis as a main driver for proliferation, differentiation, and survival. In normal physiologic conditions, BTK is activated upstream by Src family kinases Blk, Lyn, and Fyn.15,17,18BTK when activated will then phosphorylate phospholipase-Cγ leading to calcium mobilization and activation of nuclear factor-κB (NF-κB) and mitogen-activated protein (MAP) kinase pathways.19BTK is overexpressed in a variety of lymphoid malignancies, including CLL, MCL, DLBCL, WM, and multiple myeloma (MM).20,21Inhibition of BTK therefore shuts down further activation of the BCR signaling pathway and can technically arrest the proliferation of lymphoid malignancies.Ibrutinib is rapidly absorbed, with peak plasma concentrations occurring after 1 to 2 hours.22A variety of ibrutinib doses had been studied in multiple phase I clinical trials in doses ranging from 280 mg to 840 mg.13,14,23In a phase I study seeking to determine the maximum tolerated dose of ibrutinib in combination with standard doses of rituximab combined with CHOP (R-CHOP), the steady state was achieved after 1 cycle of therapy.23Doses in the ibrutinib + R-CHOP study ranged from 280 mg to 560 mg daily. The amount of time that a drug is present at the maximum concentration in serum (Tmax) values were not dose dependent, and the maximum plasma concentration of the drug (Cmax) for the 420-mg and 560-mg dose levels were 190 ng/mL and 187 ng/mL, respectively, on day 1 of cycle 2. The area under the curve (AUC) increased the dose proportionally.22AUC in the first 24 hours of therapy was 502 ng.h/mL from a single dose of 560 mg.23 AUC increased across the dose range in cycle 2 with a maximum of AUC24 with 560-mg dose at 1014 ng.h/mL and AUC 882 ng.h/mL. Plasma concentrations decreased biphasically with an initial mean half-life of 2 to 3 hours.22Mean apparent terminal half-life ranged from 4 to 8 hours. Most (>80%) of ibrutinib after single-dose administration was excreted in the feces within 48 hours and 7.8% was excreted in the urine.24Total excretion (>90%) occurred within 168 hours.

Clinical Studies

Ibrutinib binds reversibly to plasma proteins at 97% in vitro and has a volume of distribution at steady state (Vdss) of 683 L.16 Ibrutinib is metabolized primarily by CYP3A4 and, to a minor extent, by CYP2D6.25There was no difference between poor and extensive CYP2D6 metabolizers and unchanged ibrutinib exposure.24Ibrutinib’s half maximal inhibitory concentration is 0.5 nmol/L.15Ibrutinib when combined with R-CHOP showed that BTK was >90% occupied at the 560-mg dose level, 4 hours after receiving the first dose.23These data follow another pharmacodynamics study, which showed that at 2.5 mg/kg, >95% of BTK occupancy occurred 4 hours post dose.22Nearly complete occupancy was observed in patients with AUCs exceeding 160 ng.h/mL. No decrease was observed in immunoglobulin levels over the course of 12 cycles. There was an observed decrease in anti-immunoglobulin E (IgE)-stimulated basophil degranulation.Chronic lymphocytic leukemia (Download TABLE 1).

Ibrutinib’s activity as a single agent was evaluated in patients with relapsed or refractory CLL or with small lymphocytic lymphoma (SLL) through a phase Ib/II clinical trial.13In this study, 85 patients were enrolled, 65% of whom had advanced disease. Two-thirds of the patients were also considered to have high-risk disease (ie, with 17p13.1 or 11q22.3 deletions). The median number of prior treatments was 4 (range 1-12). The patients were each assigned to 1 of 3 cohorts: the first 2 groups (n = 51) received ibrutinib at 420 mg daily, and the third cohort of patients received ibrutinib at 840 mg daily (n = 34). Treatment was continued until disease progression or unacceptable toxicities.

The overall response rate (ORR) was 71% for patients treated with ibrutinib at 420 mg (2 complete responses [CRs] and 34 partial responses [PR]).13Similar activity was found in patients treated at the higher dose level (71%, 24 PR). The clinical activity observed appeared to be durable. The 26-month estimated progression-free survival (PFS) was 75% and the OS rate was 83%.

This study demonstrated that ibrutinib was active irrespective of high-risk prognostic features.13For example, patients possessing a 17p13.1 deletion exhibited a 68% response rate, including 1 CR, whereas patients without the deletion showed a response rate of 71%. However, mutations in the immunoglobulin variable-region heavy-chain gene (IgVH) appeared to affect responses. Four of the 12 patients (33%) with this mutation had a PR or CR, while 53 of 69 patients (77%) without this mutation were found to have a PR or CR that was statistically significant (P= .005). In addition, ibrutinib was found to result in sustained improvement in cytopenias, which was defined as an increase of more than 50% or a hemoglobin concentration of greater than 11 g/dL, an absolute neutrophil count higher than 1500 cells/mm,3or a platelet count greater than 100,000 cells/mm.3Of note, a transient lymphocytosis was observed in these patients, which correlated with a decrease in size of lymph nodes, spleen, or both. The lymphocytosis did not elicit symptoms from patients, and resolved with continued treatment.

An additional phase II clinical trial evaluated ibrutinib in previously untreated and relapsed or refractory CLL with TP53 mutations.26The study enrolled patients over 18 years of age with CLL who had deletion 17p13.1 or aTP53mutation. Ibrutinib was administered at a dose of 420 mg orally once daily until disease progression or unacceptable toxicity.

The study enrolled 51 patients with CLL who had theTP53deletion or mutation, 35 with previously untreated CLL, and 16 with relapsed or refractory CLL.26Most patients enrolled had unmutated IgVH and/or advanced Rai-stage disease. In addition, 47 patients were identified as having deletion 17p13.1, and 4 had aTP53mutation. At the time of follow-up (24 weeks), 48 of the patients (15 with relapsed/refractory and 33 with untreated CLL) were evaluable for response. An objective response was noted in 44 patients, with 24 patients having a PR and 20 patients with a PR and lymphocytosis. Eighteen of the 33 previously untreated patients had a PR. Of the 15 patients with relapsed or refractory CLL, 12 demonstrated an objective response, 6 had a PR, and 6 had a PR and lymphocytosis. The authors also noted that the depth and rate of responses increased with time. For example, PR was recorded in 6 patients at 8 weeks and in 24 patients at 24 weeks.

In addition, all tissue compartments demonstrated rapid disease control with at least a 50% mean reduction of tumor burden in both the lymph nodes and spleen at 8 weeks.26Disease improvement was noted in the bone marrow when compared with the lymph nodes and spleen. For example, at 8 weeks, a 50% decrease in tumor burden of the bone marrow, lymph node, and spleen was documented in 16 of 36 patients, 31 of 44 patients, and 30 of 38 patients, respectively. At the completion of treatment, a 50% reduction in disease was found in the bone marrow, lymph node, and spleen in 34 of 41 patients, 42 of 45 patients, and 38 of 40 patients, respectively. At 24 months, the approximated PFS for all patients was 82%, and OS was 80% at 24 months. For patients who were previously untreated, the OS at 24 months was estimated at 84% versus 74% for patients who were previously treated.

The combination of rituximab with ibrutinib was evaluated in patients with high-risk CLL through a single-arm phase II study.27Eligible patients included those with relapsed/refractory high-risk CLL or those with previously untreated CLL with deletion 17p13.1,TP53mutation, or 11q deletion. High-risk disease was defined as having a remission less than 36 months after chemotherapy treatment. Ibrutinib was administered as 420 mg daily continuously (each cycle comprised of 28 days). Rituximab was dosed at 375 mg/m2. During the first cycle, rituximab was administered weekly.4For cycles 2 through 6, rituximab was administered once every 28 days. After completing 6 cycles, rituximab was discontinued and patients were maintained on single-agent ibrutinib until disease progression or unacceptable toxicities.

The study enrolled 40 patients, 36 of whom had previously treated high-risk CLL and 4 who had deletion 17p13.1 or aTP53mutation and had not received previous therapy.27At the time of follow-up, 39 patients were evaluable for response assessment. A PR was found in 34 (87%) of patients, and CR was found in 3 patients. Two of the patients achieving CR had deletion 17p13.1 orTP53mutation and were previously untreated. The time to achieve response was 5.72 months, and the median duration of response was 15.44 months. In addition, the 18-month PFS for all patients was 78%, and was 72.4% in patients with deletion 17p13.1 orTP53mutation. Furthermore, a sustained improvement in cytopenias was noted in 15 of 24 patients with baseline thrombocytopenia and 15 of 17 patients with baseline anemia.

Ibrutinib was compared head to head with ofatumumab in patients with CLL/SLL who had relapsed or refractory disease after at least 1 therapy.28The study enrolled 391 patients at 67 sites across the United States and Europe. Patients were stratified based on resistance to purine analogue or whether they had chromosome deletion 17p13.1. Ibrutinib was given at 420 mg daily until progression or toxicity; ofatumumab was given intravenously at 300 mg on week 1, then 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks. As a result of other phase II data, those who progressed on ofatumumab were allowed to cross over to receive ibrutinib.13,28The primary endpoint of this trial was PFS assessed by an independent review board. Treatment-related leukocytosis was not considered to be progressive disease.

Most patients had advanced disease.28In the ibrutinib group, patients had received a median of 3 prior therapies, while the ofatumumab group had received 2 prior therapies. Otherwise, baseline demographic characteristics were balanced between treatment groups. Ibrutinib therapy resulted in a longer PFS (not reached at a median follow-up of 9.4 months). In contrast, the median PFS in the ofatumumab group was 8.1 months; 57 patients in the ofatumumab group crossed over and received ibrutinib. Similar results were observed in the analysis of patients with deletion 17p13.1 treated with ibrutinib versus ofatumumab. The median PFS was not reached in the ibrutinib group and was only 5.8 months in patients treated with ofatumumab. Ibrutinib also significantly improved OS.28After 1 year, 90% of patients receiving ibrutinib were still alive compared with 81% of patients receiving ofatumumab. When data were assessed on various subgroups according to deletion 17p13.1, previous purine analogue therapy, Rai stage at baseline, and bulky disease, ibrutinib significantly improved OS in all group categories compared with ofatumumab.

Non-Hodgkin’s lymphoma (Download TABLE 2)

A phase II study assessed the efficacy of ibrutinib in relapsed or refractory MCL.29Patients were eligible for the study after a confirmed diagnosis of MCL with cyclin D1 overexpression or translocation breakpoints t(11;14) and measurable disease (lymph nodes ≥2 cm). Exposure to previous therapy was required, but patients were ineligible if they had received more than 5 therapies. Ibrutinib was administered orally at a dose of 560 mg daily.

A total of 111 patients received ibrutinib single agent, with an approximated median follow-up of 15.3 months.29A PR was observed in 47% of patients, and a CR in 21% of patients, with an ORR of 68%. These response rates were also found to improve over time. In patients with lymph nodes ≥5 cm in diameter, 63% had a response to treatment (27 of 43 patients).

The median duration of response was estimated to be 17.5 months, and the median time to response was found to be 1.9 months.29In addition, the median time to a CR was determined to be 5.5 months. Among all of the patients receiving ibrutinib, the estimated PFS was found to be 13.9 months. For those patients achieving a PR, the median PFS was found to be 17.5 months. Median PFS was not yet reached for patients attaining a CR.

Ibrutinib monotherapy was evaluated in patients with WM. Results of a phase II study resulted in FDA approval of ibrutinib in patients with this rare lymphoid disorder. The study evaluated the safety and efficacy of ibrutinib in patients with relapsed/refractory WM who had previously received 1 line of therapy.30Patients received ibrutinib 420 mg orally once daily for up to 2 years until progression or unacceptable toxicity. Sanger sequencing was performed to detect baseline MYD88 L265P and Whim-likeCXCR4mutations in patients. Both mutations are commonly found in patients with WM and had been implicated in its pathogenesis. These mutations had been associated with an increase (MYD88 L265P) or decrease (Whim-likeCXCR4) in sensitivity to ibrutinib. The study enrolled 63 patients, of whom 17 had refractory disease. The median age was 63 years, hemoglobin was 10.5 g/dL, serum immunoglobulin M (IgM) was 3610 mg/dL, and serum M-protein was 2.14 g/dL. The median number of cycles was 6 (2-15 cycles) and the ORR to ibrutinib was 81%, including 4 very good PR (VGPR), 32 PR, and 15 patients with minimal response (no complete response was seen). When the clinical data were reported, 11 patients had stable disease and continued to receive ibrutinib. Responses correlated withCXCR4mutations but not withMYD88mutations. Patients with wild-type CXCR4 had a response rate of 77% versus a mutated rate of 30%. Surrogate markers, such as decreases in serum IgM, M-protein and increases in hemoglobin, improved in wild-type CXCR4. These patients also had peripheral lymphocytosis.

Subsequent studies evaluated the safety and efficacy of incorporating ibrutinib into standard chemo-immunotherapy regimens in B-cell malignancies. A phase I/Ib trial evaluated the addition of ibrutinib to rituximab and bendamustine in patients with relapsed or refractory NHL.14Patients were assessed for maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). A total of 46 patients were evaluated, including 17 patients with MCL, 16 with DLBCL, and 12 with FL. Patients were at least 18 years of age and had received at least 1 prior therapy, with the exception of patients with MCL, who were allowed to be treatment naïve (n = 5). Prior therapy with rituximab and bendamustine was not an exclusion criterion. Of the 43 patients who had previous therapy, the median number of therapies was 3 and 38% were refractory to previous therapy.

Patients were treated at 2 dosing levels. Dose level 1 consisted of ibrutinib 280 mg daily on days 1 through 28.14 Dose level 2 used ibrutinib at 560 mg daily on days 1 through 28. Six patients were treated at dose levels 1 and 2, with MTD defined as the highest dose level where less than or equal to 1 of 6 patients experienced DLT. After MTD was determined, 3 cohorts of 10 patients with either FL, DLBCL, or MCL were treated with ibrutinib at the MTD or at the recommended phase II dose, if MTD was not reached. In both dose levels, rituximab was given on day 1 at 375 mg/m2and bendamustine at 90 mg/m2on days 1 and 2. Growth factor use and dose reductions were allowed for grade 3 or 4 neutropenia for cycles 2 through 6.

A total of 33 patients responded to therapy and 52% achieved a CR.14Thirteen patients with MCL, 5 with DLBCL, and 5 with FL had a CR. The median time to response was 2.8 months and median time to CR was 2.9 months. The median duration of response was not reached at time of publication (2.8-28 months). Of the patients who did respond, 6 patients have progressed and 2 have died. Median PFS and OS were not reached. Patients completed a median of 8 cycles of therapy (1-34 cycles), with 35% receiving therapy at cycles 7-34. Ten patients received pegfilgrastim, with 4 patients requiring bendamustine dose reduction and 18 patients requiring ibrutinib dose reductions.

Ibrutinib was evaluated in combination with standard R-CHOP21 in patients with previously untreated CD20-positive B-cell lymphoma in an open-label, phase I/IIb study.23Eligible patients had DLBCL, MCL, or FL. Rituximab and CHOP chemotherapy were administered at standard doses on day 1 of a 21-day cycle for 6 to 8 cycles. Ibrutinib was dosed daily beginning on day 3 of the first cycle. The study was divided into a dose-escalation phase (part 1) and an efficacy-safety phase (part 2, only for DLBCL patients). Seventeen patients were enrolled in part 1 of the study, 7 at the 280 mg-dose level, 4 at the 420 mg dose level, and 6 at the 560 mg dose level.

Dosing and Administration

All the patients enrolled had newly diagnosed lymphoma and most had stage IV disease.23The study enrolled 33 patients in phase II of the study and their median age was 60.2 years. Most patients (73%) in both phases of the trial had DLBCL. In the study, 29 patients completed 6 cycles of therapy, 4 patients prematurely discontinued (3 from adverse events: gastritis, rituximab infusion reaction, and 1 death), and 1 discontinued for noncompliance. The 2 patients who did not complete part 1 of the trial included the patient with compliance issues and the patient with rituximab infusion reaction. Of those with DLBCL, 88% of patients (n = 24) completed 6 cycles of therapy. Of all the evaluable patients, 94% achieved a response to therapy, with 72% having a CR. Activity was observed in both subtypes to DLBCL: germinal center B-cell (GCB) or non-GCB DLBCL.Ibrutinib is FDA approved for the treatment of relapsed/refractory MCL, relapsed/refractory CLL/ SLL, or CLL/SLL with 17p deletion, and for WM.16Ibrutinib is dispensed in 140-mg capsules, requiring patients to take multiple capsules per dose. The approved dosing for CLL and WM is 420 mg by mouth daily and for MCL is 560 mg daily. Patients should take ibrutinib with a glass of water and should not crush, break, or open the capsules. Ibrutinib’s Cmax was 2 times higher and AUC was 1.65 times higher after being administered with food, likely because of first-pass metabolism.31Investigators believe, however, that the effects of food on absorption do not require any consideration to time of administration. If a dose is missed, the dose can be taken the same day, if remembered.16Extra doses should not be taken to make up for a missed dose.

Adverse Reactions

Ibrutinib should be interrupted for any grade 3 or greater nonhematologic or neutropenic infection, or for grade 4 hematologic toxicities.16Once symptoms resolve to at least grade 1, ibrutinib can be resumed at the previous dose. If toxicity reoccurs, the dose can be reduced by 140 mg. A further reduction may be considered, if necessary. After 2 dose reductions, ibrutinib should be discontinued. Renal clearance is not a major factor in elimination, so no renal adjustment of dose is warranted.24Ibrutinib has not been studied in renal failure requiring dialysis. Because ibrutinib is metabolized through the liver, there are dosing adjustments recommended for patients with Child-Pugh Class A hepatic impairment at baseline.16The recommended starting dose is 140 mg daily. Use is not recommended for Child-Pugh Class B and C.Compared with chemotherapy traditionally used to treat NHL, ibrutinib is a well-tolerated alternative. Concomitant chemotherapy should be carefully considered when attributing side effect profiles to ibrutinib. Mild grade 1-2 toxicities included nausea and vomiting (15%-59%), diarrhea (23%-55%), fatigue (18%-28%), peripheral edema (28%), constipation (25%), pyrexia (22%), arthralgia (22%), and respiratory symptoms, including pneumonia (13%-33%).13,23,28,29,32Most grade 1 and 2 side effects did not require any additional treatment. In a phase II trial, 57% of patients taking ibrutinib experienced grade 3 and 4 adverse events.28Most common grade 3 and 4 side effects were hematologic, with thrombocytopenia (6%-11%) and neutropenia (16%) the most common.28,29The most common grade 3 and 4 nonhematologic toxicities were pneumonia (6%), fatigue (5%), dyspnea (4%), and diarrhea (2%).

Basal-cell carcinoma and squamous cell carcinomas were reported in 4% of patients taking ibrutinib, and 3% of patients developed nonskin cancers developed during the course of the clinical trials.28Other more rare side effects included atrial fibrillation (3%-9%) and ocular toxicity (3%). Ibrutinib induced atrial fibrillation in about 5% of patients in a long-term observational follow-up, occurring anywhere from 2 months to 101 months after initiation of therapy.33Incidence may be higher based on the lack of routine screening. Echocardiographic studies showed mild to severe left atrial dilatation as well as moderate left ventricular failure in some patients. The etiology of atrial fibrillation is thought to be through inhibition of the cardiac PI3K-Akt signaling pathway.34In addition, 23% of patients in an observation study were found to have isolated systolic hypertension with increases of systolic blood pressure >20 mm Hg.33

Drug Interactions


Clinical Pearls

  • Ibrutinib is a novel inhibitor of Bruton’s tyrosine kinase (BTK) that is administered orally once a day.
  • Ibrutinib is well tolerated and its side effect profile is manageable compared with traditional chemotherapy.
  • Ibrutinib has evidence of activity in a variety of B-cell, non-Hodgkin’s lymphoma, including MCL, CLL, WM, and subtypes of diffuse large B-cell lymphoma (DLBCL; ie, activated B-cell DLBCL).

Hematologic side effects are common with ibrutinib, including cytopenias. Other side effects include petechiae (14%), bruising, and other bleeding events. There have been several cases of subdural hematomas, with and without concomitant anticoagulation use.28,29Ibrutinib has been shown to cause collagen-mediated inhibition of platelet aggregation ex vivo.35and has been shown to affect the platelet adhesion to the Von Willebrand factor (VWF) at arterial sheer rate because of its inhibition of BTK.36These explanations may suggest the cause of the bleeding events beyond thrombocytopenia observed in patients treated with ibrutinib. Rates of neutropenia varied from trial to trial; however, when ibrutinib was administered alone, grade 3 or higher neutropenia was about 16%.28,29Serum IgG, IgA, and IgM levels remained unchanged after therapy.29Ibrutinib should be avoided with major CYP3A4 inducers or inhibitors because they significantly increase or decrease its Cmax and AUC, respectively.16,25Concomitant administration with ketoconazole (a strong CYP3A4 inhibitor) resulted in a 24-fold and a 29-fold increase in ibrutinib’s AUC and Cmax, respectively.25Administration with rifampin (a strong CYA4 inducer) resulted in a 10-fold and a 13-fold decrease on ibrutinib AUC and Cmax values, respectively. There was no change in half-life with either interaction. Consider making dose adjustments in patients requiring medications with moderate to strong CYP3A4-inducing or -inhibiting properties. Despite no formal publications studying dose adjustments, it is recommended that the dose of ibrutinib be decreased to 140 mg daily when given with moderate inhibitors.16While ibrutinib is a relatively new option in the treatment of B-cell NHL, it has convincing antitumor activity as a single agent in a wide variety of B-cell lymphoma subtypes and is a viable therapeutic option for patients. It has shown to have activity in WM, CLL, MCL, and DLBCL, as well as subtypes of NHL. It has the added benefit of being administered orally once a day and having a better-tolerated side effect profile compared with other agents. On the other hand, clinicians must be cautious when prescribing this agent in frail elderly patients with comorbid conditions, because drug interactions alter ibrutinib levels and may result in excessive toxicity. Additional preclinical and clinical studies will further define its role as a single agent or in combination with rituximab, chemotherapy, or other targeted agents in the management of patients with treatment-naïve and relapsed or refractory B-cell lymphoma.


  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015.CA Cancer J Clin.2015;65(1):5-29.
  2. Piro LD, White CA, Grillo-Lopez AJ, et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma.Ann Oncol. 1999;10(6):655-661.
  3. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.J Clin Oncol.1998;16(8):2825-2833.
  4. Leget GA, Czuczman MS. Use of rituximab, the new FDA-approved antibody.Curr Opin Oncol. 1998;10(6):548-551.
  5. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti- CD20 monoclonal antibody and CHOP chemotherapy.J Clin Oncol.1999;17(1):268-276.
  6. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.Blood. 2005;106(12):3725-3732.
  7. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma.Blood. 2005;105(4):1417-1423.
  8. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002;346(4):235-242.
  9. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG).Blood. 2006;108(13):4003-4008.
  10. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group.Lancet Oncol.2006;7:379-391.
  11. Fisher RI, LeBlanc M, Press OW, et al. New treatment options have _changed the survival of patients with follicular lymphoma.J Clin Oncol. 2005;23(33):8447-8452.
  12. Liu Q, Fayad L, Cabanillas F, et al. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center.J Clin Oncol.2006;24(10):1582-1589.
  13. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.N Engl J Med.2013;369(1)(:32- 42.
  14. Maddocks K, Christian B, Jaglowski S, et al. A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma.Blood. 2015;125(2):242- 248.
  15. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.Proc Natl Acad Sci U S A.2010;107(29):13075-13080.
  16. Czuczman MS. Sixth International Workshop on Non-Hodgkin Lymphoma: 16-17 November 2007, Boston, USA.Leuk Lymphoma.2008;49(suppl 1):4-6.
  17. Afar DE, Park H, Howell BW, et al. Regulation of Btk by Src family tyrosine kinases. Mol Cell Biol. 1996;16(7):3465-3471.
  18. Cheng G, Ye ZS, Baltimore D. Binding of Bruton’s tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.Proc Natl Acad Sci U S A.1994;91(17):8152-8155.
  19. Humphries LA, Dangelmaier C, Sommer K, et al. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker.J Biol Chem.2004;279(36):37651-37661.
  20. Winer ES, Ingham RR, Castillo JJ. PCI-32765: a novel Bruton’s tyrosine kinase inhibitor for the treatment of lymphoid malignancies.Expert Opin Investig Drugs. 2012;21(3):355-361.
  21. Wiestner A. Targeting B-Cell receptor signaling for anticancer therapy: the Bruton’s tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies.J Clin Oncol.2013;31(1):128-130.
  22. 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(1):88-94.
  23. Younes A, Thieblemont C, Morschhauser F, et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study.Lancet Oncol.2014;15(9):1019-1026.
  24. Scheers E, Leclercq L, de Jong J, et al. Absorption, metabolism, and excretion of oral 14C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men.Drug Metab Dispos. 2015;43(2):289- 297.
  25. De Jong J, Murphy J, Sukbuntherng J, et al. Effect of cyp3a perpetrators on ibrutinib exposure in normal healthy subjects.Clin Pharmacol Ther.2014;95:S32.
  26. 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;16(2):169- 176.
  27. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study.Lancet Oncol.2014;15(10):1090-1099.
  28. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.N Engl J Med.2014;371(3):213-223.
  29. 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(6):507-516.
  30. Treon SPT, Yang CK, Cao G, et al. A Prospective Multicenter Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Patients With Relapsed or Refractory Waldenstrom’s Macroglobulinemia. 2013 ASH Annual Meeting, 2013.
  31. de Jong J, Sukbuntherng J, Skee D, et al. Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients.Cancer Res.2014;74:4637, Abstract 4637.
  32. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.Lancet Oncol.2014;15(1):48-58.
  33. Binsah G, Philip TA, Ferrajoli A, et al. An observational study of the occurrence of atrial fibrillation and hypertension in patients treated with ibrutinib.Blood. 2014;124:21.
  34. McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling.Blood. 2014;124:3829-3830.
  35. Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation [published online August 20, 2014].Leukemia. doi:10.1038/leu.2014.247.
  36. Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions.Blood. 2014; 124(26):3991-3995.

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