Drugs DOI 10.1007/s40265-015-0380-3

ADIS DRUG EVALUATION

Ibrutinib: A Review of Its Use in Patients with Mantle Cell Lymphoma or Chronic Lymphocytic Leukaemia Esther S. Kim1 • Sohita Dhillon1

Ó Springer International Publishing Switzerland 2015

Abstract Ibrutinib (ImbruvicaÒ) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton’s tyrosine kinase (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with \10 % of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. The manuscript was reviewed by: J. Delgado, Department of Hematology, Hospital Clinic, IDIBAPS, Barcelona, Spain; M.M. Dreyling, Department of Medicine III, University Hospital, LudwigMaximilians University, Munich, Germany; S. P. Mulligan, Royal North Shore Hospital, Sydney, NSW, Australia; N. Reddy, Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. & Esther S. Kim [email protected] 1

Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand

Ibrutinib in MCL or CLL: a summary Irreversibly inhibits Bruton’s tyrosine kinase Induces high overall response in patients with relapsed/refractory MCL Significantly prolongs progression-free survival and overall survival and improves partial response rates in patients with relapsed/refractory CLL (including those with del 17p) compared with ofatumumab Has an acceptable tolerability profile

1 Introduction Mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL) are two B-cell malignancies that affect more men than women, with a median age at diagnosis that is commonly over 60 years [1, 2]. MCL is a rare type of B-cell non-Hodgkin lymphoma (NHL) that accounts for approximately 6 % of all NHLs [1]. MCL is typically an aggressive cancer with a poor prognosis, high recurrence rates and a median overall survival (OS) of up to 5 years [3, 4]. However, significant variability of the disease course is recognized [5]. CLL is the most prevalent type of leukaemia in Western countries [2]. CLL is typically an indolent cancer that is not curable with conventional therapies and has an estimated median OS of 10.7 years [6, 7]. A variable disease course is recognized in CLL as well [2]. In CLL, approximately 3–8 % of patients at diagnosis or treatment initiation have deletions in the short arm of chromosome 17 (del 17p) that usually result in the removal of an allele in TP53 (the gene encoding for the critical

E. S. Kim, S. Dhillon

tumour suppressor p53) [8]. Patients with del 17p or TP53 mutation have a poor prognosis (median OS of 2–3 years) and respond poorly to conventional therapy [9]. Although many patients with MCL or CLL respond well to initial therapy, patients ultimately relapse [4, 10]. Treatment for patients with relapsed/refractory disease is determined by the duration of response after first-line therapy and should be adapted to the performance status and age of the patient [5, 11]. Treatment options for these patients include immunochemotherapy (e.g. rituximabcontaining regimens) and molecular targeting agents (e.g. temsirolimus approved in the EU, and bortezomib and lenalidomide approved in the USA) for patients with MCL, and chemotherapy, immunochemotherapy and monoclonal antibodies (e.g. rituximab, ofatumumab) for patients with CLL [11, 12]. More recently, an improved understanding of the pathogenesis of these B-cell malignancies has led to the development of new targeted treatment options for patients with MCL or CLL [13, 14]. With aberrant B-cell antigen receptor (BCR) signalling implicated in the pathogenesis of several B-cell malignancies, one such strategy is inhibition of Bruton’s tyrosine kinase (BTK) [7, 15]. BTK is a member of the Tec kinase family that transmits signals from various cell surface receptors, most prominently from the BCR [7, 16]. BTK is thought to play a role in the intermediate stages of the BCR signalling cascade and is commonly overexpressed in MCL and CLL [17–19]. Ibrutinib (ImbruvicaÒ) is a first-in-class, potent, orally administered, covalent inhibitor of BTK that has been approved in the EU and USA for the treatment of patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation [20–22]. This article reviews the efficacy and tolerability of ibrutinib in the treatment of patients in these populations and briefly summarizes its pharmacology. Ibrutinib has recently been approved for Waldenstro¨m’s macroglobulinaemia (WM) in the USA [20], and a type II variation application to include WM as a new indication is pending in the EU [23], but this indication will not be discussed further as it is outside the scope of this review.

cysteine residue (Cys-481) in the BTK active site and irreversibly inhibits BCR signalling downstream of BTK [24]. Ibrutinib reduced the phosphorylation of BTK, PLCc2, AKT and ERK in CLL cells in vivo [15, 25] and in MCL cells in vitro [26]. In addition, ibrutinib reduced the expression of Ki67, a marker of proliferation, in MCL and CLL cells in vivo [15, 25, 26]. Ibrutinib inhibited BCR and NF-jB signalling in CLL cells not only in the peripheral blood but also in the bone marrow and lymph nodes [25]. In patients with B-cell malignancies, ibrutinib showed a BTK active-site occupancy rate of C95 % as early as 4 h after administration [27, 28]. Consistent with an irreversible mechanism, BTK active-site occupancy was fully maintained for C24 h [27]. In CLL patients, ibrutinib showed time-dependent biological changes that likely occurred between 1 and 15 days after administration [15]. 2.2 Lymphocytosis Lymphocytosis is a frequently encountered class effect of BCR-targeting small molecules, including ibrutinib [29]. In clinical studies in MCL and CLL patients, treatment with ibrutinib caused transient and reversible increases in lymphocyte counts (i.e. absolute lymphocyte count [5000/lL and increase of C50 % from baseline), often associated with a rapid reduction in lymphadenopathy [20, 28–31]. Lymphocytosis occurred early during treatment and usually resolved within a median of 8 weeks in MCL patients and 18.7 weeks in CLL patients [21]. This lymphocytosis is thought to reflect a redistribution of malignant lymphocytes between different anatomical compartments, probably because of a disruption of BCR-mediated stromal chemotaxis and adhesion [27, 29]. It is very clear and recommended that in the absence of other clinical findings, ibrutinib-induced lymphocytosis should not be considered progressive disease [21, 29]. Prolonged lymphocytosis (lymphocytosis not normalizing or improving to \50 % of baseline within 12 months) following ibrutinib treatment has also been observed in some patients but does not appear to adversely affect progression-free survival (PFS) [32]. 2.3 Resistance

2 Pharmacodynamic Properties 2.1 Mechanism of Action The phosphorylation and activation of BTK by Src family protein kinases (e.g. LYN, SYK) leads to PLCc2 phosphorylation, calcium mobilization and activation of downstream pathways (e.g. AKT, MAP kinase, NFjB) that lead to changes that promote cell differentiation, proliferation and survival [15]. Ibrutinib binds covalently to a

Few patients with CLL have had a relapse on ibrutinib [33], but recent data suggest that primary and secondary resistance is common in MCL patients treated with ibrutinib [34]. In both MCL and CLL, a cysteine-to-serine missense mutation at the ibrutinib binding site of BTK (BTKC481S) has been identified following a durable response [33, 35]. This mutation prevents irreversible binding of ibrutinib to BTK and results in a reduced degree of B-cell receptor signalling-inhibition by ibrutinib in mutant

Ibrutinib: A Review

BTK compared with nonmutant BTK [33]. In CLL patients with acquired resistance to ibrutinib, PLCc2 mutations (e.g. L845F, R665W, S707Y mutations) have been identified in addition to BTKC481S [33]. These PLCc2 mutations are believed to be gain-of-function mutations that confer resistance to ibrutinib by allowing BCR-mediated activation that is independent of BTK [33]. The absence of BTKC481S in MCL patients with primary resistance or a transient (\5 months) response to ibrutinib and the absence of both BTK or PLCc2 mutations before ibrutinib exposure in CLL patients who develop acquired resistance suggest alternative mechanisms contributing to primary or rapid resistance to ibrutinib [33, 35].

There is potential for clinically relevant interactions between strong or moderate CYP3A4 inhibitors or inducers, and P-glycoprotein substrates with a narrow therapeutic window [20, 21]. Azole antifungals [e.g. fluconazole, itraconazole, ketoconazole, voriconazole (CYP3A inhibitors)] may markedly increase ibrutinib plasma concentrations. In addition, the use of ibrutinib in patients receiving anticoagulants (e.g. warfarin) or antiplatelets may increase the risk of bleeding. Local prescribing information should be consulted for further information on potential interactions and precautions for use [20, 21].

4 Therapeutic Efficacy 3 Pharmacokinetic Properties 4.1 In Patients with Relapsed/Refractory MCL The pharmacokinetic properties of ibrutinib do not differ significantly between patients with different B-cell malignancies [21, 28]. Oral ibrutinib is rapidly absorbed, with a median time to peak plasma ibrutinib concentration (Cmax) of 1–2 h [20, 21, 27, 28]. Ibrutinib exposure increased proportionally with daily doses from 420 mg up to 840 mg [20, 21, 28]. Compared with the fasted state, the administration of ibrutinib with food increased the area under the plasma concentration-time curve by twofold and mean Cmax by two- to fourfold [20]. Ibrutinib had reversible plasma protein binding of 97.3 % and an apparent volume of distribution at steady state of &10,000 L [20, 21]. Ibrutinib is metabolized in the liver primarily by cytochrome P450 (CYP) 3A4, and to a minor extent by CYP2D6 [20, 21]. The elimination of ibrutinib, mainly in the form of metabolites, is primarily via faeces. After a single oral dose of radiolabelled ibrutinib, most (90 %) of the drug was eliminated within 168 h, with 80 % of the dose excreted in the faeces and\10 % in the urine [20, 21]. Ibrutinib has a half-life of 4–13 h [21] and an apparent oral clearance of &1000 L/h in a fed state and &2000 L/h in a fasted state [20]. Ibrutinib exposure is increased in patients with hepatic impairment; therefore, dosage adjustments are required or the drug should not be used in patients with hepatic dysfunction [20, 21]. No specific studies have been conducted in patients with renal impairment [21]; however, as ibrutinib has minimal renal clearance, dosage adjustments are not needed in patients with mild to moderate dysfunction [21]. The pharmacokinetics of ibrutinib were not altered to a clinically relevant extent based on age, gender and body weight [20, 21]. The safety and efficacy of ibrutinib in paediatric patients have not been established. Ibrutinib can cause fetal harm, so women should avoid becoming pregnant during ibrutinib therapy [20, 21].

The efficacy of oral ibrutinib in adult patients with relapsed/refractory MCL was evaluated in an open-label, phase II trial [31]. Key inclusion criteria included a confirmed diagnosis of MCL and at least one prior line of treatment, with either no partial or better response to or disease progression after the most recent treatment regimen [31]. At baseline, 89 % of patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, 39 % had bulky disease (C5 cm) and 49 % were high-risk patients (as assessed by the simplified MCL international prognostic index) [21, 31]. The median time since diagnosis was 42 months, and patients had received a median of three prior treatments [21, 31]. Patients were classified as either bortezomib-naı¨ve (no prior bortezomib therapy or less than two complete cycles; n = 65) or bortezomib-experienced (at least two cycles; n = 50) and received ibrutinib 560 mg once daily until disease progression or unacceptable tolerability [31]. Efficacy analyses included all patients who received at least one dose of ibrutinib and had at least one post-baseline efficacy assessment (n = 111). The primary endpoint was overall response rate (ORR), as assessed by the revised International Working Group criteria for NHL [31]. At an estimated median follow-up of 15.3 months, the ORR with ibrutinib was 68 % (complete response rate in 21 % and partial response rate in 47 % of patients) and the estimated median response duration was 17.5 months [31]. These results were consistent with an independent review committee’s evaluation, which showed a response rate of 69 % (complete response rate in 21 % and partial response rate in 48 % of patients) and an estimated median response duration of 19.6 months. Moreover, the response to ibrutinib was consistent across patient subgroups, regardless of prior treatment (e.g. to bortezomib) or underlying risk/ prognostic factors (e.g. bulky disease). The estimated

E. S. Kim, S. Dhillon

median PFS with ibrutinib was 13.9 months, and the median OS was not reached. The estimated OS rate at 18 months was 58 % [31]. The efficacy of ibrutinib was sustained during longerterm therapy. At an estimated median follow-up of 26.7 months, the ORR in ibrutinib recipients was 67 % (complete response rate in 22.5 %), and the median response duration was 17.5 months (abstract presentation) [36]. The median PFS with ibrutinib was 13 months and the median OS was 22.5 months (24-month Kaplan–Meier PFS and OS rates of 31.1 and 47.3 %) [36]. 4.2 In Patients with Relapsed/Refractory CLL The efficacy of ibrutinib in patients with relapsed/refractory CLL was shown in an open-label, multicentre, phase Ib/II trial [28]. Since then, results of a randomized, openlabel, multicentre, phase III trial (RESONATE) [30] have been published. Therefore, this section will focus on the phase III trial. The RESONATE trial enrolled patients with CLL or small lymphocytic lymphoma (SLL), who had received at least one prior treatment and were not considered appropriate candidates for purine analogue treatment [30]. At baseline, all patients had an ECOG performance status of 0 or 1, 58 % of patient had bulky disease (C5 cm) and 32 % of patients had del 17p [21, 30]. The median time since diagnosis was 91 months, and the median number of prior treatments was two [21]. Patients were randomized to oral ibrutinib 420 mg once daily (n = 195) until unacceptable toxicity or disease progression occurred or intravenous ofatumumab (n = 196) for up to 24 weeks (300 mg as initial dose for week 1, followed by 2000 mg once weekly for 7 weeks then once every 4 weeks for 16 weeks, consistent with local labelling) [30]. Of note, the RESONATE study excluded patients receiving warfarin but allowed patients to receive other forms of anticoagulation. During the study, a protocol amendment allowed ofatumumab recipients with disease progression to cross over to receive ibrutinib treatment. The primary endpoint was the duration of PFS as assessed by the independent review committee [based on the criteria of the International Workshop on CLL (with clarification that patients with lymphocytosis in the setting of improvement in other parameters should not be considered to have progressive disease)], and the intentto-treat population was used for the efficacy analysis [30]. At a median follow-up of 9.4 months, in the overall population (n = 391), ibrutinib significantly (p \ 0.001) prolonged the duration of PFS, with a 78 % reduction in the risk of disease progression or death compared with ofatumumab [median PFS not reached with ibrutinib vs. 8.1 months with ofatumumab; hazard ratio (HR) 0.22; 95 % CI 0.15–0.32] [30]. OS was also significantly

(p = 0.005) prolonged with ibrutinib relative to ofatumumab (HR 0.43; 95 % CI 0.24–0.79), corresponding to a 57 % reduction in the risk of death (median OS was not reached in either treatment group). This difference in survival may have been greater, but the detection of this difference was limited due to 57 subjects that crossed over to receive ibrutinib. In addition, the ORR (as assessed by independent reviewers) was significantly (p \ 0.001) higher with ibrutinib than with ofatumumab [43 vs. 4 %; odds ratio (OR) 17.4; 95 % CI 8.1–37.3]. All responses were partial responses in both treatment groups, and an additional 20 % of ibrutinib recipients had a partial response with lymphocytosis, bringing the total response rate with ibrutinib to 63 % [30]. The treatment benefit with ibrutinib in terms of PFS was observed regardless of baseline characteristics or molecular features, including in patients with (HR 0.25; 95 % CI 0.14–0.45) or without (HR 0.19; 95 % CI 0.12–0.32) del 17p13.1 [30]. In patients with del 17p (a subgroup with a poor prognosis), median PFS was not reached in ibrutinib recipients (n = 63) compared with a median PFS of 5.8 months in ofatumumab recipients (n = 64). At 6 months, 83 % of ibrutinib recipients in this subgroup were alive without disease progression compared with 49 % of ofatumumab recipients [30]. The ORR was 47.6 % in the ibrutinib group, compared with 4.7 % in the ofatumumab group, with partial responses seen in all responders [20]. Of note, a phase II study (RESONATE-17) of oral ibrutinib 420 mg in patients with relapsed/refractory CLL or SLL with del 17p (n = 144) showed consistent results with 79.3 % of patients progression free at 12 months (abstract presentation) [37]. The benefit of ibrutinib therapy was sustained at a median follow-up of 16 months, with significantly longer PFS in ibrutinib than ofatumumab recipients (median PFS not reached vs. 8.1 months; HR 0.106; 95 % CI 0.073–0.153; p \ 0.0001) [abstract presentation] [38]. At week 24, the proportion of patients with a clinically meaningful improvement (C3 points) in Functional Assessment of Chronic Illness Therapy–Fatigue scores did not significantly differ between ibrutinib and ofatumumab recipients (59 vs. 46 %) [39]. A clinically meaningful improvement in scores for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 was seen in 46 % of ibrutinib recipients and 40 % of ofatumumab recipients [39].

5 Tolerability Ibrutinib had an acceptable tolerability profile in clinical studies in patients with relapsed/refractory MCL or CLL. In pooled data (n = 357) from three trials in patients with

Ibrutinib: A Review

MCL or CLL, the most common adverse reactions (incidence C20 %) with ibrutinib were bruising, constipation, diarrhoea, musculoskeletal pain, nausea, neutropenia, pyrexia and upper respiratory tract infection [21]. The most common grade 3 or 4 adverse reactions (incidence C5 %) were anaemia, neutropenia, pneumonia and thrombocytopenia. Adverse reactions (including infections and haematoma) resulted in treatment discontinuations in 6 % of ibrutinib recipients, and 8 % of patients required dosage adjustments because of these events [21]. In patients with CLL, at least one adverse event was reported in 99 % of ibrutinib recipients and 98 % of ofatumumab recipients after a median treatment exposure of 8.6 and 5.3 months, respectively [30]. Although the median treatment exposure was longer in ibrutinib recipients than in ofatumumab recipients, there was no adjustment for exposure time. Any-grade adverse events occurring in [15 % of patients in either group are shown in Fig. 1. The most commonly occurring any-grade nonhaematological adverse event with ibrutinib was diarrhoea (48 %, of which 4 % were grade 3–4), and the most commonly occurring any-grade haematological adverse event with ibrutinib was anaemia (23 %, of which 5 % were grade 3–4) (Fig. 1). Any-grade adverse events occurring at a numerically higher incidence with ibrutinib relative to ofatumumab included all infections (70 vs. 54 %), all bleeding-related events (44 vs. 12 %), pyrexia (24 vs. 15 %), blurred vision (10 vs. 3 %), rash (8 vs. 4 %), atrial fibrillation (5 vs. 0.5 %) and cataracts (3 vs. 1 %). Any-grade adverse events occurring at a numerically higher incidence with ofatumumab relative to ibrutinib included infusion reactions (28 vs. 0 %), night sweats (13 vs. 5 %), peripheral sensory neuropathy (13 vs. 4 %), pruritus (incidence not stated) and urticaria (incidence not stated) [30]. Grade 3 or 4 adverse events were reported in 51 % of ibrutinib recipients and in 39 % of ofatumumab recipients in this study [30]. The only grade 3 or 4 adverse event occurring in [15 % of patients in either group was neutropenia (16 vs. 14 %). Other grade 3 or 4 adverse events occurring in numerically more ibrutinib than ofatumumab recipients included atrial fibrillation (3 vs. 0 %) and diarrhoea (4 vs. 2 %). Major haemorrhage (adverse event of grade C3 severity or resulting in red cell transfusion or hospitalization) occurred in 1 and 2 % of patients in the corresponding treatment groups. Serious adverse events were reported in 42 % of ibrutinib and 30 % of ofatumumab recipients. The most commonly occurring serious adverse events included infections such as pneumonia (9 % of ibrutinib recipients vs. 6 % of ofatumumab recipients) and lung infections (3 vs. 0 %) and cardiac disorders such as atrial fibrillation (3 vs. 0.5 %). Fatal adverse events (most commonly infections) occurred in 4 % of ibrutinib recipients and 5 % of ofatumumab recipients. Relatively

few patients in either study group withdrew from treatment because of adverse events (4 vs. 4 %), and adverse events resulted in dose reductions in only 4 % of ibrutinib recipients [30]. The tolerability profile of ibrutinib was similar at a median follow-up of 16 months with a median treatment duration of 16 months in ibrutinib recipients and 5 months in ofatumumab recipients (abstract presentation) [38]. Diarrhoea (51 %), fatigue (33 %) and nausea (32 %) were the most common any-grade adverse events and neutropenia (18 %) was the most common grade 3 or 4 adverse event. Atrial fibrillation (any grade) was observed in 7 % of patients receiving ibrutinib. Ibrutinib was discontinued because of adverse events in 7 % of patients [38]. The tolerability profile of ibrutinib in patients with MCL was generally similar to that discussed above [31, 36], with infection (78 %) and diarrhoea (54 %) being the most common any-grade adverse events during a median 27 months of follow-up (abstract presentation) [36]. At 27 months, any-grade bleeding occurred in 50.5 % of patients and treatment was discontinued because of adverse events in 11 % of patients [36].

6 Dosage and Administration The recommended dosage of oral ibrutinib is 560 mg once daily for MCL and 420 mg once daily for CLL [20, 21] until disease progression or intolerance by the patient [21]. Upon toxicity resolution, dosing guidelines allow for ibrutinib reinitiation at the original starting dose [20, 21]. Dosage adjustments or drug avoidance may be required in patients with hepatic dysfunction [20, 21]. Dosage adjustments are not needed in patients with mild to moderate renal dysfunction [21]. Women should avoid becoming pregnant during ibrutinib therapy [20, 21]. Local prescribing information should be consulted for further information, including dosage adjustments, interactions, contraindications, warnings and precautions.

7 Current Status of Ibrutinib in MCL and CLL Ibrutinib is a first-in-class irreversible inhibitor of BTK (Sect. 2) approved in the EU for the treatment of adult patients with relapsed/refractory MCL, CLL with at least one prior therapy or previously untreated CLL (unsuitable for chemo-immunotherapy) in the presence of del 17p or a TP53 mutation [21]. Ibrutinib is approved in the USA for the treatment of MCL or CLL patients who have received at least one prior therapy and for the treatment of CLL patients with del 17p [20].

E. S. Kim, S. Dhillon 60

Ibrutinib (n = 195) Ofatumumab (n = 191)

50

Percentage of patients

Fig. 1 Incidence of any-grade adverse events occurring in [15 % of patients with relapsed/refractory chronic lymphocytic leukaemia receiving oral ibrutinib or intravenous ofatumumab (median treatment exposure of 8.6 months in ibrutinib recipients and 5.3 months in ofatumumab recipients) in the RESONATE trial [30]. URTI upper respiratory tract infection

40 30 20 10 0

Non-haematological adverse events

In clinical studies, ibrutinib induced a high ORR in patients with relapsed/refractory MCL (phase II study; Sect. 4.1) and significantly prolonged PFS and significantly improved the partial response rate and OS in patients with relapsed/refractory CLL (RESONATE study; Sect. 4.2), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with \10 % of patients requiring dosage adjustments or treatment discontinuation (Sect. 5). Major haemorrhage was an adverse event of interest with ibrutinib [30]. In the RESONATE study, all bleeding-related events of any grade occurred at a numerically higher incidence with ibrutinib compared with ofatumumab, but the incidence of major haemorrhage was similar between the two (Sect. 5). Unexpected major bleeding was not seen with ibrutinib in the RESONATE study because of adherence to precautions regarding the use of anticoagulants and antiplatelets as well as perioperative drug-withholding guidelines [30]. Another adverse event of interest with ibrutinib is atrial fibrillation [40]. Any-grade, grade 3–4 and serious atrial fibrillations occurred at a numerically higher incidence with ibrutinib compared with ofatumumab in the RESONATE study (Sect. 5). One potential explanation, based on a study of rat myocytes, is the inhibition of cardioprotective PI3K-Akt signalling by ibrutinib [40]. However, the effect of ibrutinib and the role of BTK on human myocytes has not been demonstrated [41]. Further studies on the impact of ibrutinib on cardiac function are warranted [40]. Given ibrutinib’s efficacy and tolerability, the recent European Society for Medical Oncology guidelines for MCL [12] and the National Comprehensive Cancer

Haematological adverse events

Network guidelines for NHL [11] include ibrutinib as a treatment option for relapsed/refractory MCL [11, 12], relapsed/refractory CLL (category 1 recommendation) [11] and as first-line therapy for CLL with del 17p [11]. Head-to-head trials comparing ibrutinib with other approved agents for relapsed/refractory MCL (e.g. bortezomib, lenalidomide, temsirolimus) are needed. Although ibrutinib seems to double the ORR and PFS compared with these other agents based on individual trials, the treatment populations are not directly comparable and comparisons across trials should be made with caution [42]. Evidence from an indirect analysis using matching-adjusted indirect comparisons suggested that, in patients with relapsed/refractory MCL, ibrutinib recipients had better odds of achieving an ORR than bortezomib (OR 3.62; 95 % CI 1.18–11.14) or FCM (fludarabine, cyclophosphamide, mitoxantrone; OR 3.22; 95 % CI 1.01–10.26) recipients (abstract presentation) [43]. Results from additional direct comparative phase III trials [NCT01646021 (ibrutinib vs. temsirolimus in relapsed/refractory MCL), NCT01973387 (ibrutinib vs. rituximab in relapsed/refractory CLL/SLL)] are awaited with interest. Although ibrutinib was approved based on results of trials assessing the drug as monotherapy [20, 21], combination therapies are being explored for improved disease control. Ibrutinib therapy is associated with lymphocytosis, a class effect of BCR-targeting molecules (Sect. 2.2). Ibrutinib-induced lymphocytosis is generally asymptomatic and not considered progression of the disease; however, long-term treatment may be necessary and chances of achieving complete remission may be reduced [13]. Therefore, the use of ibrutinib in combination with CD20

Ibrutinib: A Review

antibodies [e.g. rituximab, ofatumumab, obinutuzumab (also known as GA101)], which can clear malignant cells from peripheral blood, is being explored [13, 44]. In addition, ibrutinib combination studies are also underway to see if the addition of ibrutinib to conventional therapies would prevent or treat resistant disease [10, 33]. A phase II study examining ibrutinib in combination with rituximab in high-risk CLL patients [patients with high-risk cytogenetic abnormalities (del 17p, del 11q, TP53 mutation) or poor response to prior chemoimmunotherapy] showed an ORR of 95 %, 18-month PFS in 78 % of all patients, 18-month OS of 84 % in all patients and a short duration of ibrutinib-induced lymphocytosis [45]. Preliminary results from a phase II study examining ibrutinib in combination with rituximab in relapsed MCL showed an ORR of 87 % at a median follow-up time of 6.5 months [46]. Of note, ibrutinib demonstrated efficacy especially in patients with lower Ki-67 (ORR 100 % in all 33 patients with Ki-67 lower than 50 %) [46]. The phase III HELIOS trial is examining whether or not ibrutinib added to BR (bendamustine and rituximab) would provide prolonged disease control compared with BR alone in relapsed/refractory CLL or SLL [47]. A phase II study comparing ibrutinib monotherapy to ibrutinib in combination with rituximab in patients with relapsed CLL is ongoing (NCT02007044). Results are awaited with interest. Preliminary evidence suggests that ibrutinib is associated with better health outcomes (projected life years and qualityadjusted life years) than ofatumumab in CLL patients [48] and other treatments commonly used in relapsed or refractory MCL patients [49] (abstract presentations). The final results of these ongoing studies are awaited with interest. In conclusion, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and previously untreated CLL in the presence of del 17p or a TP53 mutation. Data selection sources: Relevant medical literature (including published and unpublished data) on ibrutinib was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 8 March 2015], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Ibrutinib, Imbruvica, PCI-32765. Study selection: Studies in patients with chronic lymphocytic (lymphoid) leukaemia and mantle cell lymphoma who received ibrutinib. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of

the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author(s) on the basis of scientific and editorial merit. Esther Kim and Sohita Dhillon are salaried employees of Adis/Springer.

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