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

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

Bruton&rsquo;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 Waldenstr&ouml;m&rsquo;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&rsquo;s antitumor activity as a single agent or in combination with other agents in patients with CLL/MCL or WM.

Non-Hodgkin&rsquo;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 Waldenstr&ouml;m&rsquo;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.

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.

On 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&rsquo;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.

Ibrutinib&rsquo;s empiric formula is C25H24N6O2 and its molecular weight is 440.50.

Bruton&rsquo;s tyrosine kinase is a Tec family kinase that is involved in the BCR signaling pathway.

The 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.

BTK when activated will then phosphorylate phospholipase-C&gamma; leading to calcium mobilization and activation of nuclear factor-&kappa;B (NF-&kappa;B) and mitogen-activated protein (MAP) kinase pathways.

BTK is overexpressed in a variety of lymphoid malignancies, including CLL, MCL, DLBCL, WM, and multiple myeloma (MM).

Inhibition 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.

A variety of ibrutinib doses had been studied in multiple phase I clinical trials in doses ranging from 280 mg to 840 mg.

In 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.

Doses 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.

AUC 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.

Mean 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.

Total excretion (>90%) occurred within 168 hours.

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.

There was no difference between poor and extensive CYP2D6 metabolizers and unchanged ibrutinib exposure.

Ibrutinib&rsquo;s half maximal inhibitory concentration is 0.5 nmol/L.

Ibrutinib when combined with R-CHOP showed that BTK was >90% occupied at the 560-mg dose level, 4 hours after receiving the first dose.

These data follow another pharmacodynamics study, which showed that at 2.5 mg/kg, >95% of BTK occupancy occurred 4 hours post dose.

Nearly 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.

Ibrutinib&rsquo;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.

In 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]).

Similar 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.

For 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 (

) 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 (

= .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,

or a platelet count greater than 100,000 cells/mm.

Of 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.

The study enrolled patients over 18 years of age with CLL who had deletion 17p13.1 or a

mutation. 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 the

deletion or mutation, 35 with previously untreated CLL, and 16 with relapsed or refractory CLL.

Most 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 a

mutation. 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.

Disease 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.

Eligible patients included those with relapsed/refractory high-risk CLL or those with previously untreated CLL with deletion 17p13.1,

mutation, 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/m

. During the first cycle, rituximab was administered weekly.

For 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 a

mutation and had not received previous therapy.

At 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 or

mutation 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 or

mutation. 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.

The 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.

The primary endpoint of this trial was PFS assessed by an independent review board. Treatment-related leukocytosis was not considered to be progressive disease.

In 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.

After 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.

A phase II study assessed the efficacy of ibrutinib in relapsed or refractory MCL.

Patients 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 &ge;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.

A 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 &ge;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.

In 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.

Patients 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-like

mutations 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 (

) 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 with

mutations. 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.

Patients 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 na&iuml;ve (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/m

on 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.

Thirteen 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.

Eligible 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.

All the patients enrolled had newly diagnosed lymphoma and most had stage IV disease.

The 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.

Ibrutinib 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&rsquo;s Cmax was 2 times higher and AUC was 1.65 times higher after being administered with food, likely because of first-pass metabolism.

Investigators 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.

Extra doses should not be taken to make up for a missed dose.

Ibrutinib should be interrupted for any grade 3 or greater nonhematologic or neutropenic infection, or for grade 4 hematologic toxicities.

Once 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.

Ibrutinib 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.

The 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%).

Most 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.

Most common grade 3 and 4 side effects were hematologic, with thrombocytopenia (6%-11%) and neutropenia (16%) the most common.

The 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.

Other 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.

Incidence 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.

In addition, 23% of patients in an observation study were found to have isolated systolic hypertension with increases of systolic blood pressure >20 mm Hg.

Ibrutinib is a novel inhibitor of Bruton&rsquo;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&rsquo;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.

Ibrutinib has been shown to cause collagen-mediated inhibition of platelet aggregation ex vivo.

and has been shown to affect the platelet adhesion to the Von Willebrand factor (VWF) at arterial sheer rate because of its inhibition of BTK.

These 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%.

Serum IgG, IgA, and IgM levels remained unchanged after therapy.

Ibrutinib should be avoided with major CYP3A4 inducers or inhibitors because they significantly increase or decrease its Cmax and AUC, respectively.

Concomitant administration with ketoconazole (a strong CYP3A4 inhibitor) resulted in a 24-fold and a 29-fold increase in ibrutinib&rsquo;s AUC and Cmax, respectively.

Administration 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.

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. 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-na&iuml;ve and relapsed or refractory B-cell lymphoma.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015.

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&rsquo;s lymphoma.

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.

Leget GA, Czuczman MS. Use of rituximab, the new FDA-approved antibody.

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.

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.

Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma.

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.

Articles

Clinical Articles

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.

Ibrutinib in the Management of B-cell Malignancies

: Brentuximab vedotin is an antibody-drug conjugate that targets CD30-expressing cells and has demonstrated single-agent clinical efficacy in pivotal phase II trials in relapsed or refractory Hodgkin lymphoma after autologous stem cell transplant and in relapsed or refractory systemic anaplastic large cell lymphoma. Brentuximab vedotin carries an adverse event (AE) profile that differs from those of traditional monoclonal antibody therapies. Herein we discuss the management of common AEs in addition to symptoms that may accompany rare AEs associated with brentuximab vedotin.

Published, sponsored clinical trial studies of single-agent brentuximab vedotin were surveyed to identify the most commonly reported AEs. Reporting rates for rare AEs were estimated from cases drawn from the Seattle Genetics drug safety database using the current version of the Medical Dictionary for Regulatory Activities.

: Peripheral neuropathy and neutropenia were identified as the most frequently reported AEs across the published clinical trials. Rare AEs included progressive multifocal leukoencephalopathy, Stevens-Johnson syndrome/toxic epidermal necrolysis, pancreatitis, pulmonary toxicity, and hepatotoxicity; reporting rates for these rare AEs (<2%) were within or below population-specific background ranges reported in the literature.

: Common AEs associated with brentuximab vedotin, such as peripheral neuropathy and neutropenia, are often manageable with modifications to dose and schedule. While rare AEs have been reported at rates similar to or below background, vigilant monitoring is necessary to detect and address these serious potential complications.

The antibody-drug conjugate (ADC) brentuximab vedotin is composed of a CD30-specific monoclonal antibody, cAC10, attached to the microtubule disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable dipeptide linker.

Brentuximab vedotin binds to and is internalized by CD30-expressing cells, where it is trafficked to the lysosome. The dipeptide linker is selectively cleaved within the lysosome, releasing MMAE into the cell, where it binds microtubules and disrupts the microtubule network, inducing G2/M cell cycle arrest and apoptosis.

Single-agent brentuximab vedotin was studied at a dose of 1.8 mg/kg administered as a 30-minute intravenous infusion every 3 weeks in 2 multinational, single-arm, open-label, phase II pivotal trials.

In one trial, brentuximab vedotin was administered to 102 patients with relapsed or refractory Hodgkin lymphoma (HL) after autologous stem cell transplant. In this study, 75% of patients achieved an objective response (n = 76; 95% confidence interval [CI], 64.9-82.6), with a complete remission (CR) rate of 34% (n = 35; 95% CI, 25.2-44.4). Another pivotal phase II trial was conducted to evaluate single-agent brentuximab vedotin in 58 patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). In that study, 86% of patients achieved an objective response (95% CI, 74.6-93.9), with a CR rate of 57% (95% CI, 43.2- 69.8). Efficacy results for both trials are summarized in

Table 1. Brentuximab Vedotin Clinical Trials: Design, Baseline Patient Characteristics, and Efficacy Outcomes [CLICK TO DOWNLOAD]

Because it contains a cytotoxic agent, the adverse events (AEs) profile of brentuximab vedotin differs from that of unconjugated monoclonal antibodies. Appropriate surveillance and management of the AEs associated with brentuximab vedotin are important to enable patients to benefit fully from this novel therapy. The objective of this publication is to outline strategies for the management of common and rare AEs that may arise during treatment with brentuximab vedotin.

We present a 67-year-old female with CD30-positive diffuse large B-cell lymphoma, previously treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and RICE (rituximab, ifosfamide, carboplatin, etoposide), who could not undergo autologous stem cell transplant (ASCT) because of insufficient stem cell collection. The patient&rsquo;s disease relapsed 2 months after chemotherapy, and she enrolled in a clinical study of brentuximab vedotin. Additional complicating medical issues included polymyositis on active steroid therapy, documented stage III nonalcohol steatohepatitis, and hypogammaglobulinemia on replacement intravenous immunoglobulin (IVIG) treatment. The patient received 2 cycles of brentuximab vedotin at a dose of 1.8 mg/kg and achieved a CR after the second cycle. She also experienced infusion-related reactions (IRRs), including shortness of breath, and was subsequently premedicated with hydrocortisone, diphenhydramine, famotidine, and acetaminophen.

The patient was unable to continue treatment on the clinical study because of persistently elevated transaminases, and she experienced disease progression 3 months after her removal from the study. Upon enrollment in a retreatment study, the patient was treated with 1.8 mg/kg brentuximab vedotin and again achieved CR after the second cycle. The dose was reduced to 1.2 mg/kg after the third cycle because of repeat elevation of transaminases. After dose reduction, peak transaminases were reduced from approximately 400 U/L to the mid-100 U/L range. The patient entered observation after completing 11 cycles on this protocol.

The patient&rsquo;s disease progressed 3 months after she stopped therapy. She is currently being treated with brentuximab vedotin, off protocol, at a dose of 1.2 mg/kg. The patient again experienced elevated transaminases, along with worsening of peripheral sensory neuropathy from grade 1 to grade 2/3. By lengthening the dosing interval from 3 weeks to 5 weeks, and subsequently further, transaminase levels improved to the 100 U/L range, and peripheral neuropathy improved to grade 1. To date, the patient has completed 20 cycles off protocol. At the time of this publication, the patient was being treated with brentuximab vedotin for an off-label indication in the United States.

We surveyed published, sponsored clinical trial data to identify the most frequently reported AEs associated with single-agent use of brentuximab vedotin. These studies included the phase II pivotal trials in relapsed or refractory HL and sALCL, a phase II study of extended treatment in relapsed or refractory CD30-positive hematologic malignancies, and a phase II study in patients with T-cell lymphoma (

). Common AEs that occurred with a frequency of at least 25% in any study were included in this report. To estimate reporting rates for serious AEs, we tabulated cases drawn from the Seattle Genetics drug safety database (DSB) using the current version of the Medical Dictionary for Regulatory Activities (MedDRA) at the time of each search. Search strategies included Standardized MedDRA Queries (SMQs), where available, as well as custom search queries. Search results include all safety reports in the DSB up to August 18, 2014.

Recommendations for surveillance and management of AEs were drawn from internal databases and from real-life practices based on our clinical experiences with brentuximab vedotin. Unless otherwise noted, recommendations on dose modifications reflect the current US Prescribing Information (USPI); guidance may vary in other regions.

Common adverse events associated withbrentuximab vedotin

Peripheral neuropathy was the most commonly reported AE in most published clinical trials on brentuximab vedotin (

). Peripheral neuropathy, as identified by SMQ, was reported in approximately 55% of patients and was the primary cause of treatment-related discontinuations in the pivotal phase II trials in HL and sALCL.

Overall, 10% to 15% of patients experienced grade 3 events; no grade 4 events were reported. The peripheral neuropathy reported in the pivotal trials was cumulative and primarily sensory in nature, although motor neuropathy was experienced by 13% of patients (Seattle Genetics, Inc, unpublished data). Preexisting peripheral neuropathy, primarily grade 1, was present in 24% of patients in these studies. In the pivotal trials, the median time to first onset of any peripheral neuropathy was 12.4 weeks (approximately 4 cycles). Peripheral neuropathy (SMQ) led to dose delays in 15% of patients, to dose reductions in 9% of patients, and to treatment discontinuations in 12% of patients across the 2 trials. Partial improvement (by 1 grade or more) or complete resolution of peripheral neuropathy events after dose holding or dose reduction were reported in approximately 80% of patients, with a median time to improvement or resolution of 13.2 weeks and 9.9 weeks in HL and sALCL, respectively.5,6 Peripheral neuropathy was also observed in other published clinical trials (

TABLE 2. Drug-Related Adverse Events of Brentuximab Vedotin Occurring in &ge;25% of Patients in Any Published Clinical Trial

Risk factors for peripheral neuropathy include diabetes mellitus, vitamin B deficiency, glutamine deficiency, hypothyroidism (commonly seen in patients after field irradiation), and prior or concomitant use of other treatments associated with peripheral neuropathy.

Patients who experience symptoms of peripheral neuropathy may describe tingling or a feeling of numbness that starts at the tips of their fingers or toes. Some patients may also report muscle aches or overall muscle weakness that is related to neuropathy. Appropriate assessment and documentation of preexisting peripheral neuropathy before the start of therapy are essential to establish baseline neurologic status. Current grading of peripheral neuropathy, as defined in the National Cancer Institute&rsquo;s Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, is listed in

. Note that these criteria differ from those listed in version 3.0, which was used to assess neuropathy in the pivotal trials. Neuropathy should be assessed before administration of every dose, and assessments should remain consistent among examinations. However, it is often useful to introduce new tasks during assessments so that deficits may be identified. For example, a patient who is able to fasten buttons at each examination may be unable to pick up a coin from a flat surface or to write legibly. Patients should be educated on symptoms of peripheral neuropathy, and it may be useful to remind them of symptoms reported at baseline for comparison to their current status.

TABLE 3. Definitions and Grading of Peripheral Sensory and Motor Neuropathy (reproduced from NCI Common Terminology Criteria for Adverse Events, Version 4.03)

The peripheral neuropathy associated with brentuximab vedotin is generally reversible and may often be managed with modifications to dosing and schedule. In patients who present with new or worsening grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to grade 1 or to baseline and then restarted at 1.2 mg/kg. Patients who successfully resume treatment at the reduced dose should not undergo dose escalation to 1.8 mg/kg, because symptoms may return. Treatment should be discontinued in patients with grade 4 peripheral neuropathy. We also recommend that patient education on management of neuropathy include information on hydration and maintaining adequate electrolyte levels per institutional guidelines, in addition to guidance on keeping extremities warm.

Both clinical trial and practical experience suggest that it is preferable to address peripheral neuropathy at lower grades of severity. Indeed, our experience is that neuropathy improves more quickly when dosing is held at the emergence of grade 2 neuropathy, before it worsens to grade 3. Dosing may then be resumed sooner, although at the reduced dose, which may result in better therapeutic effects. Data from the pivotal trials also support initiation of dose holding at the emergence of grade 2 rather than grade 3 neuropathy. In those trials, the median time to resolution or improvement of peripheral neuropathy events with a worst severity of grade 2 was 12.1 weeks compared with 15.6 weeks for events with a worst severity of grade 3 (

FIGURE. Time to resolution or improvement

of peripheral neuropathy events in phase II pivotal trials.

With patient education and proper management, peripheral neuropathy should not prevent patients from receiving treatment to disease progression. In an extension study of patients with relapsed or refractory CD30-positive hematologic malignancies, 19 patients received a median of 24 cycles of brentuximab vedotin (range, 17-42) over a median of 21 months (range, 14-32).

Peripheral sensory neuropathy was reported in 74% of patients, with first onset occurring within cycles 1 through 16 in 53% of patients. Dose reductions and delays per protocol occurred in 37% and 74% of patients, respectively.

Based on our clinical experience, alterations in dosing interval may be considered after resumption of dosing at 1.2 mg/kg, particularly for patients in CR. Lengthening the dosing interval by 1 or more weeks, for example, may minimize the risk of recurrence of grade 2 or higher peripheral neuropathy events while allowing the patient to remain on treatment. It is important to note, however, that this recommendation is not detailed in the prescribing information.

Neutropenia was commonly reported across the published clinical trials and was a primary cause of dose delays (

). In the pivotal phase II trials in HL and sALCL, neutropenia, predominantly grade 3 or higher, was reported in 19% of patients and led to dose delays in 15% of patients.

The neutropenia observed in the trials was transient and did not contribute to cases of febrile neutropenia, although febrile neutropenia has been reported in postmarketing experience.

Surveillance is again crucial to ensuring safe and appropriate treatment and should include monitoring of complete blood counts prior to each dose of brentuximab vedotin. In patients with grade 3 or 4 neutropenia, more frequent monitoring is recommended. If grade 3 or 4 neutropenia develops, dosing should be suspended until neutropenia resolves to baseline or less than or equal to grade 2, and subsequently resumed at a dose of 1.2 mg/kg. In practice, we find that neutropenia often resolves by the time of the patient&rsquo;s next dose on the standard 21-day schedule; delays are typically brief. However, for the first few doses it may be useful to monitor complete blood counts mid-cycle to guard against prolonged instances of early neutropenia. Growth factor support for subsequent doses may be considered but, in our experience, has not frequently been needed.

Rash was a common AE reported in the phase II and other clinical trials. Rash, grades 1 and 2, was reported in 27% of patients in the phase II HL trial and in 31% of patients in the phase II sALCL trial.

Stevens-Johnson syndrome (SJS) was reported in 1 patient in the pivotal trials and, in combination with toxic epidermal necrolysis (TEN), occurs at a rate of less than 0.1%, accounting for all AE reporting sources (

). Nearly all of these cases were confounded by concomitant drugs known to cause SJS/TEN, including co-trimoxazole and allopurinol, as well as underlying clinical conditions such as systemic cancer and ongoing infections (Seattle Genetics, Inc, unpublished data). Rash was reported in 10% of patients in an ongoing, open-label, phase II trial evaluating brentuximab vedotin in patients with CD30-positive non-Hodgkin lymphoma.

Grade 3 macular rash was also reported in 1 patient on the same trial.

Rash was reported in 27% of patients in an open-label, phase II trial evaluating brentuximab vedotin in CD30-positive lymphoproliferative disorders and in CD30-positive mycosis fungoides.

In practice, patients may present with mild rash that is observed more frequently in sALCL than in HL. Symptomatic management with topical 1% hydrocortisone or a short course of systemic corticosteroids (eg, methylprednisolone) is often sufficient to address rash in most patients, although dose delays may be recommended for more severe cases. However, patients who present with severe rash should be monitored carefully, because SJS and TEN, while rare, are life-threatening toxicities that have occurred after exposure to brentuximab vedotin. In patients who experience these events, treatment should be discontinued and urgent medical care administered.

In the pivotal phase II trials, grade 1 or 2 IRRs were reported in 12% of patients. The most common AEs associated with IRRs were chills, nausea, dyspnea, pruritus, pyrexia, and cough.

Most IRRs reported in the pivotal trials occurred within the first 2 cycles of treatment and correlated with antitherapeutic antibody (ATA) positivity (Seattle Genetics, Inc, unpublished data). Anaphylaxis was reported in 2 patients enrolled in phase I clinical trials, and in both cases, occurred during cycle 2 (Younes et al

and unpublished data). One patient permanently discontinued treatment; the other patient received premedication and was successfully rechallenged in later cycles.

We recommend an evaluation of concomitant medications 2 weeks before initiation of therapy with brentuximab vedotin. In practice, we have observed an increase in IRRs that is specific to fluconazole, an inhibitor of CYP3A4. Discontinuing use of CYP3A4/5 inhibitors and other nonessential medications may decrease the likelihood that the patient experiences an IRR. Patients should be monitored for IRR or anaphylaxis during and after each infusion and should also be informed that symptoms associated with IRRs may occur up to 24 hours after any infusion of brentuximab vedotin. If a patient experiences an IRR, the infusion should be interrupted so that appropriate medical therapy may be instituted. Premedication with acetaminophen, an antihistamine, and a corticosteroid is recommended for subsequent infusions, and at some institutions, is administered to all patients as standard practice. Protocols for successful desensitization to brentuximab vedotin have also been developed and may be considered for patients who continue to experience hypersensitivity reactions.

If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical therapy instituted.

Rare Adverse Events Associated With Brentuximab Vedotin

Progressive Multifocal Leukoencephalopathy (PML)

PML is a demyelinating disease of the central nervous system that is caused by opportunistic infection with John Cunningham (JC) virus, a human polyomavirus. In the absence of gold standard criteria, diagnosis is generally based on a combination of clinical, radiographic, and virologic features.

Symptoms progress gradually and may include cognitive and/or speech abnormalities, visual deficits, motor weakness, sensory deficits, loss of coordination, headache, change in personality, or seizures. Patients who are immunosuppressed or have concomitant hematologic malignancies are at risk of developing PML.

PML is estimated to occur in 0.07% to 0.52% of patients with lymphoproliferative disorders who are treated with chemotherapy.

PML has been observed in patients treated with brentuximab vedotin in both clinical trials and postmarketing experience at rates of less than 0.1% (

). While the frequency of PML in patients treated with brentuximab vedotin falls within the range of background frequencies reported in this patient population, PML represents a serious potential complication that requires appropriate surveillance and patient education about potential symptoms. Dosing with brentuximab vedotin should be suspended if PML is suspected and permanently discontinued if PML is confirmed.

Acute pancreatitis is characterized by abdominal pain, nausea, and elevated pancreatic enzymes (serum lipase and/or amylase &ge;3 times the upper limit of normal).

Cases of acute pancreatitis in patients who received brentuximab vedotin have been reported in the literature and include both clinical trial and postmarketing experience.

The incidence of acute pancreatitis in the clinical trials was 0.25%, and analysis of reports from postmarketing sources yielded an estimated reporting rate of 0.16%. In most cases, patients experienced symptoms within cycle 1 or 2.

The etiology of acute pancreatitis in patients treated with brentuximab vedotin is unclear; many of the cases reported were confounded by underlying diseases or by concomitant medications known to be associated with pancreatitis. In a tissue cross-reactivity study, biotin-conjugated brentuximab vedotin did not demonstrate binding in human pancreas tissues (Seattle Genetics, Inc, unpublished data). It is possible that the hepatic excretion of MMAE in patients with biliary obstruction may lead to pancreatitis. Acute pancreatitis is estimated to occur in 4.4% to 7.7% of patients after hematopoietic stem cell transplant (HSCT).

Based on a review of cases reported to date, pancreatitis represents a potential risk after administration of brentuximab vedotin, and appropriate surveillance of symptoms is needed. While routine monitoring of serum amylase and lipase is not recommended, close monitoring for possible pancreatitis, including evaluation of serum lipase and amylase, is recommended for patients who present with severe abdominal pain. In the event that pancreatitis is diagnosed, treatment with brentuximab vedotin should be discontinued and appropriate medical care administered.

Common AEs associated with brentuximab vedotin, such as peripheral neuropathy and neutropenia, are often manageable with modifications to dose and schedule.

Treatment Strategies to Optimize Outcomes With Brentuximab Vedotin: Management of Common and Rare Toxicities

The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that are expressed in mammalian cells and are known to play an important role in intracellular signaling of different receptor tyrosine kinases and G-proteincoupled receptors.

Comprehensive reviews of the PI3K signaling pathway and its role in normal and disease states have been previously published.

Various isoforms of PI3Ks exist, including the delta (&delta;) and gamma (&gamma;) isoforms, which show a preferential expression in cells of the immune system.

Selective inhibitors of these kinases have been developed, and these agents have been used to investigate the biologic role of these isoforms in a variety of inflammatory processes and hematologic malignancies.

Role of PI3K &delta; in Normal and Disease States

Studies of genetically engineered mice that are either deficient in PI3K &delta;, or that express a catalytically inactive form, have linked this kinase to a broad range of immune cell functions, such as B-cell and T-cell activation and proliferation, and have also shown it to be a requirement for signaling in other immune cell types, such as monocytes and dendritic cells.

In mice that express a catalytically inactive form of PI3K &delta;, for example, immune responses are attenuated, and antigen signaling in both B and T cells is impaired.

B cells in these mice also show reduced immunoglobulin production, and poor proliferative responses to B-cell receptor (BCR) stimulation or CD40 in vitro.

B cells that lack PI3K &delta; also show a diminished chemotaxis response to chemokines like CXCL13.

Importantly, these experimental observations from genetically engineered mice can be replicated using small-molecule inhibitors that are specific for the PI3K-&delta; isoform.

The use of PI3K-&delta; inhibitors such as CAL-101 has also been examined in tumor cell lines and in patient samples representative of primary B-cell malignancies. These studies have demonstrated that constitutive activation of PI3K and activation of downstream effector molecules can be blocked with PI3K-&delta; inhibition, which ultimately results in the induction of apoptosis.

In addition, chronic lymphocytic leukemia (CLL) cells show high PI3K enzymatic activity and PI3K-&delta; expression, and these CLL cells can be induced to undergo apoptosis ex vivo using CAL-101, whereas this PI3K-&delta; inhibitor does not cause apoptosis in normal T cells or natural killer cells, nor does it inhibit other essential immune functions such as antibody-dependent cellular cytotoxicity.

Clinical data also show that PI3K &delta; can be effectively inhibited in vivo with CAL-101 treatment, and this has been correlated with transient lymphocytosis and reduced levels of circulating chemokines, including CCL-3, CCL-4, and CXCL-13 in patients with CLL.

Role of PI3K &gamma; in Normal and Disease States

Results from mouse models of asthma have suggested that inhibitors of the p110-&gamma; isoform of PI3K inhibit innate immune cell migration and other lymphocyte functions, for example, eosinophil recruitment.

Similar to mice with PI3K-&delta; gene inactivation, key immune cell functions, including migration, proliferation, and activation, are also observed in mice with a targeted disruption of the PI3K-&gamma; gene.

Macrophages from mice lacking PI3K &gamma;, for example, show reduced migratory capability and accumulation in response to inflammatory and chemotactic stimuli; neutrophils from these mice also displayed impaired mobility and respiratory burst capability in response to chemotactic signals.

Various isoforms of PI3Ks exist, including the delta (Î´) and gamma (Î³) isoforms, which show a preferential expression in cells of the immune system.

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