Targeting Bruton’s Tyrosine Kinase With Ibrutinib in B-Cell Malignancies Y Wang1, LL Zhang2, RE Champlin3 and ML Wang2,3 The B-cell receptor signaling pathway, which is critical to the development and maturation of normal B-cells, is emerging as an attractive therapeutic target in B-cell malignancies. Ibrutinib is a potent irreversible inhibitor of Bruton’s tyrosine kinase (Btk), a key kinase important for signal transduction in the B-cell receptor (BCR) pathway. In preclinical studies, ibrutinib potently bound to Btk, inhibited BCR signaling, and decreased tumor cell proliferation and survival in many B-cell malignancy models. Excellent safety and efficacy data in clinical trials have led to US Food and Drug Administration (FDA) approval of ibrutinib for previously treated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), as well as CLL with 17p deletion. Ongoing clinical studies have also demonstrated great potency of ibrutinib in treating other types of non-Hodgkin’s lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and €m’s macroglobulinemia (WM). Combination of ibrutinib with chemoimmunotherapy and other promising novel Waldenstro agents in B-cell malignancy therapy has also been under clinical investigation. INTRODUCTION
B-cell receptor (BCR) signaling pathway is imperative for cellular selection, development, maturation, and survival of normal Bcells. Bruton’s tyrosine kinase (Btk) is a key kinase downstream of the B-cell receptor that is critical to the BCR signaling. Lack of Btk function leads to the development of X-linked agammaglobulinemia (XLA), which is characterized by deficiency of mature B-cell and antibody production and recurrent infections. In recent years, upregulated BCR signaling has been recognized as an important pathogenesis mechanism in B-cell malignancies. Small molecule inhibitors targeting key kinases in the BCR pathway, in particular Btk, have been developed and are under investigation in both preclinical and clinical studies. By far, the most well studied agent is ibrutinib, formerly known as PCI-32765, a covalent, irreversible inhibitor of Btk. In preclinical studies, it has been shown to have activity against a variety of B-cell malignancies in cell lines, patient samples, and animal models. In clinical studies, ibrutinib is well-tolerated and has shown great efficacy in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and some other types of non-Hodgkin’s lymphoma (NHL). Furthermore, ibrutinib has gained US Food and Drug Administration (FDA) approval for use in patients with CLL and MCL who have received at least one prior therapy, and in patients with CLL with 17p deletion. Many clinical studies are ongoing to further evaluate the safety and efficacy of ibrutinib in
B-cell malignancies, as a single agent or in combination with chemoimmunotherapy or other small molecule signal transduction inhibitors. In this review, we provide a brief overview of the BCR pathway and Btk, and summarize available preclinical and clinical data on the first-in-class Btk inhibitor ibrutinib in B-cell malignancy. B-CELL RECEPTOR SIGNALING PATHWAY
The BCR signaling pathway is critical to the development and maturation of B-cells. A simplified diagram of this pathway is shown in Figure 1 and described below.1,2 The membrane-bound BCR associates with heterodimeric CD79a and CD79b proteins, which contain immunoreceptor tyrosine-based activation motifs that are crucial for BCR signaling initiation. After BCR aggregation, immunoreceptor tyrosine-based activation motifs are phosphorylated primarily by Src-family tyrosine kinases, such as Lyn. Phosphorylated immunoreceptor tyrosine-based activation motifs serve as a scaffolding platform for engaging and activating SH2 domains containing kinases, including Syk. The BCR co-receptor CD19 is also phosphorylated by Lyn upon BCR ligation, and phosphorylated CD19 recruits the SH2 domain containing kinase phosphatidylinositol-3-kinase (PI3K). Active PI3K phosphorylates the plasma membrane lipid phosphatidylinositol 4, 5-bisphosphate to generate phosphoinositide phosphatidylinositol-3, 4, 5-trisphosphate, which is essential
1 Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA; 2Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 3Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Correspondence: ML Wang ([email protected])
Received 1 December 2014; accepted 28 January 2015; advance online publication 2 February 2015. doi:10.1002/cpt.85 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
455
Figure 1 B-cell receptor (BCR) pathway.
for recruitment of the Btk through its pleckstrin homology domain. In addition, activated Syk phosphorylates the B-cell linker protein BLNK, which is directly recruited to BCR through its interaction with CD79a. Phosphorylated BLNK associates with both Btk and phospholipase g2 (PLCg2) through their SH2 domains, and Btk is then phosphorylated and activated by Syk, while PLCg2 is dually phosphorylated and activated by Syk and Btk. Activated PLCg2 cleaves phosphatidylinositol 4, 5-bisphosphate and generates inositol triphosphate and diacylglycerol. Inositol triphosphate generation causes calcium mobilization from both intracellular stores and extracellular influx, and Ca21 together with diacylglycerol then activates PKCb, which, in turn, phosphorylates a variety of downstream substrates and activates multiple signaling pathways. Importantly, IjB kinase is activated 456
downstream of PKCb, leading to IjB phosphorylation and dissociation of a key transcription factor NF-jB, which translocates into the nucleus and mediates transcriptional regulation of many genes. In addition, Ca21 in conjunction with calmodulin also activates another transcription factor nuclear factor of activated T-cells, which also regulates expression of a variety of genes. BRUTON’S TYROSINE KINASE
Among the many kinases involved in BCR signaling, Btk is a key molecule that is critical to normal B-cell development. Its essential role is demonstrated in the inherited syndrome XLA, which was initially described by Dr. Ogden Carr Bruton in 1952.3 XLA is a human immunodeficiency syndrome characterized by failure of pre-B-cells in the bone marrow to develop into circulating mature B-cells. This VOLUME 97 NUMBER 5 | MAY 2015 | www.wileyonlinelibrary/cpt
of eight dogs with NHL (follicular large cell and diffuse immunoblastic types).10 Subsequent preclinical studies demonstrated that ibrutinib was active in a variety of B-cell malignancies including CLL, MCL, diffuse large B-cell lymphoma (DLBCL), and Waldenstr€om’s macroglobulinemia (WM). CHRONIC LYMPHOCYTIC LEUKEMIA
Figure 2 Ibrutinib binds to the ATP-binding site of Bruton’s tyrosine kinase (Btk). Domain structure of Btk (a) and chemical structure of ibrutinib (b).
disorder is caused by a single gene defect of Btk on X chromosome.4 This remarkable association of Btk with the pathogenesis of XLA supports its critical role as a key regulator of B-cell development. Btk contains five domains: a pleckstrin homology domain; a Tec homology domain, which includes the Btk homology, and polyproline region domains; two Src homology domains (SH2 and SH3); and a tyrosine kinase domain (Figure 2). These domains can recognize various signaling molecules, allowing Btk to function in the center of the BCR signaling pathway. TARGETING BTK IN B-CELL MALIGNANCIES
The BCR signaling pathway is implicated in the pathogenesis of B-cell malignancies, including CLL and NHL.5–8 The essential role of Btk in the BCR pathway and B-cell survival, demonstrated in the pathogenesis of XLA, makes it an attractive therapeutic target for B-cell malignancies. A number of Btk inhibitors have been developed, among which ibrutinib (Figure 2), formerly known as PCI-32765, is by far the most well studied agent in both preclinical and clinical settings. Ibrutinib (Imbruvica) is a first-in-class Btk inhibitor, manufactured by Pharmacyclics (Sunnyvale, CA) and co-developed in partnership with Janssen Pharmaceuticals (Beerse, Belgium)/Johnson & Johnson (New Brunswick, NJ). Like other Btk inhibitors, ibrutinib was designed to inhibit Btk by selectively interacting with an ATP-binding site in the tyrosine kinase domain, thereby preventing Btk phosphorylation and activation. Specifically, it irreversibly binds to Cys-481 in the active site of Btk (Figure 2), resulting in its sustained inhibition. Ibrutinib is available orally, and is characterized by its high potency with an IC50 of 0.5 nM, and high selectivity toward Btk over other kinases.9 Many preclinical and clinical studies have demonstrated its great promise in the treatment of various B-cell malignancies. PRECLINICAL STUDIES
The efficacy of ibrutinib in B-cell malignancies was first established in spontaneous canine lymphoma models. Daily oral administration of ibrutinib resulted in partial response in three CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
A number of elegant preclinical studies have demonstrated the activity of ibrutinib against CLL. Herman et al.11 first showed that ibrutinib induced apoptosis and inhibited activationinduced proliferation of CLL cells in vitro. Ponader et al.12 reported that ibrutinib inhibited CLL cell survival and migration in response to homing chemokines, and downregulated secretion of BCR-dependent chemokines by CLL cells. Importantly, they demonstrated that ibrutinib profoundly inhibited CLL progression in an adoptive transfer TCL1 mouse model of CLL. Woyach et al.13 demonstrated that ibrutinib inhibited the development of CLL and improved survival in TCL1 transgenic mice, and improved overall survival of CB17/SCID mice transplanted with TCL1 leukemic spleen lymphocytes. Herman et al.14 showed that ibrutinib decreased proliferation and induced apoptosis of CLL cells, and reduced tumor burden in the NOD/ scid/gcnull mouse xenograft model. Potential ibrutinib-containing combination therapy for CLL has also been studied preclinically. Promising candidates to combine with ibrutinib included proteasome inhibitors,15 Bcl-2 inhibitors,16 and IRAK1/4 kinase inhibitors.17 These combinations were somewhat better studied in other B-cell malignancies and are described below. In addition, Wu et al.18 reported at the ASH 2014 meeting that whereas ibrutinib and Wnt signaling inhibitor dimethyl fumarate both had single-agent activity against CLL in patient-derived tumor cells and Rag22/2gc2/2 mice engrafted with human CLL cells, the combination achieved higher therapeutic efficacy. MANTLE CELL LYMPHOMA
Ponader et al.19 first reported at the ASH 2011 meeting that ibrutinib was effective in inhibiting proliferation of MCL cell lines, most prominently JVM-2 and Mino. They also showed that ibrutinib inhibited IgM-stimulated secretion of chemokines CCL3 and CCL4 by MCL cell lines. Ou et al.20 also reported single-agent activity of ibrutinib against a variety of MCL cell lines at the same meeting. Cinar et al.21 showed that ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration-dependent and time-dependent manners, and induced a concentration-dependent apoptosis in both cell lines. At the ASH 2013 meeting, Ou et al.22 reported that, in an huSCID MCL mouse model, ibrutinib mobilized MCL cells from the lymphoid tissue into peripheral blood, leading to MCL cytotoxicity and increased mouse survival. A number of preclinical studies have explored potential ibrutinib-containing combination strategy for MCL therapy, with proteasome inhibitors and Bcl-2 inhibitors being the most studied candidates. Brett et al.15 reported at the ASH 2013 meeting that a combination of ibrutinib with proteasome inhibitors carfilzomib and bortezomib, as well as Bcl-2 inhibitor ABT-199, 457
displayed robust synergistic cytotoxicity toward MCL cell lines. The synergistic effect between ibrutinib and carfilzomib was also seen in samples from patients with MCL and CLL.15 Consistent with these findings, Dasmahapatra et al.23 demonstrated that coadministration of ibrutinib and bortezomib synergistically increased apoptosis of MCL cells. The same combination strategy was also effective against both activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtype of DLBCL cells.23 Zhao et al.24 also demonstrated that the ibrutinib and ABT-199 combination displayed strong synergistic effects in MCL cell lines as well as primary cells from patients with recurrent MCL. Portell et al.16 reported, again at the ASH 2014 meeting, the synergistic effect of ibrutinib and carfilzomib or ABT-199 on apoptosis of circulating tumor cells from patients with MCL. Abundant data, as described above, support that the combination of ibrutinib with proteasome inhibitors or Bcl-2 inhibitors makes a promising therapeutic strategy for MCL. Another promising combination strategy is ibrutinib plus CD20 antibodies. At the ASH 2014 meeting, Zhang et al.25 demonstrated that the ibrutinib and rituximab combination synergistically induced apoptosis of MCL cell lines and primary MCL cells, and eradicated MCL cells and prolonged animal survival in the hu-SCID MCL mouse model. Other combination strategies are also being explored. At the ASH 2012 meeting, Sahakian et al.26 reported that, although ibrutinib and HDAC6 inhibitor ACY1215 both decreased viability of MCL cell lines in vitro, the combination resulted in a threefold increase in apoptosis induction. Synergistic effect between ibrutinib and another HDAC inhibitor, vorinostat, in inducing apoptosis and growth inhibition was reported at the ASH 2014 meeting by Hagiwara et al.27 Tabe et al.28 showed at the ASH 2014 meeting that the combination of ibrutinib with KPT-330, a selective inhibitor of nuclear export, synergistically inhibited cyclin D1 expression and reduced tumor cell proliferation. DIFFUSE LARGE B-CELL LYMPHOMA
Davis et al.8 first showed activity of ibrutinib against ABC subtype of DLBCL with chronic active BCR signaling. Consistently, Zoellner et al.29 reported at the ASH 2011 meeting that ibrutinib reduced cell growth in ABC but not GCB DLBCL cell lines. A number of preclinical studies of combining ibrutinib with other agents, including PI3K inhibitor, Syk inhibitor, mTOR inhibitor, Bcl-2 inhibitor, and lenalidomide, have been conducted in DLBCL with promising results reported. Combination of ibrutinib with either mTOR inhibitor temsirolimus or PI3K inhibitor Cal101 showed additive effect in ABC and synergistic effect in GCB DLBCL cell lines.29 Ezell et al.30 found that the combination of ibrutinib with AZD2014, an mTOR catalytic inhibitor, were highly synergistic in killing the ABC subtype of DLBCL cell lines. This combination induced apoptosis both in vitro and in vivo, and resulted in tumor regression in the OCI-LY10 xenograft model. Kuo et al.31 reported at the ASH 2014 meeting that the combination of ibrutinib and Bcl-2 inhibitors completely inhibited tumor growth in murine models of ABC DLBCL, and Bcl-2 or Syk inhibitors resensitized ibrutinib-resistant cells. Yang et al.32 reported that ibrutinib synergized with lenalidomide in killing ABC DLBCL cells both in vitro and in the OCI-LY10 xenograft 458
model. In a recent unbiased screening, ibrutinib was also shown to interact favorably with PI3K-Akt-mTOR signaling inhibitors, other BCR signaling inhibitors, Bcl-2 family inhibitors, and certain chemotherapy agents in ABC DLBCL.33 Although most available data were on ABC DLBCL, use of ibrutinib might be potentially extended to other subtypes of DLBCL as well. In GCB DLBCL cell lines, Zheng et al.34 showed that ibrutinib inhibited proliferation, induced apoptosis, and attenuated production of the CCL3 and CCL4 chemokines. In double-hit DLBCL, the combination of ibrutinib and carfilzomib synergistically inhibited cell proliferation and induced cell death in three double-hit DLBCL cell lines (CJ, RC, and U-2973).35 This finding provides promise to the therapy of double-hit DLBCL, which is notoriously resistant to chemotherapies. € WALDENSTROM’S MACROGLOBULINEMIA
The L265P mutation of MYD88, an adapter that promotes Tolllike receptor and interleukin-1 receptor signaling through the IRAK1/4/TRAF6/NF-jB pathway, was reported in over 90% of patients with WM. At the ASH 2014 meeting, Yang et al.36 reported that the L265P mutant induced robust Btk phosphorylation in WM cells, and ibrutinib treatment resulted in significant WM tumor cell killing, and ibrutinib was synergistic with an IRAK1/4 kinase inhibitor in killing WM cells. This combination was also shown to be effective in ABC DLBCL and CLL with MYD88 L265P mutation, which occurred in 30% and 6.25% of patients, respectively.17,37 Chitta et al.38 reported at the ASH 2014 meeting that the Bcl-2 inhibitor ABT-199 resensitized and synergized with ibrutinib in ibrutinib-resistant WM cells, suggesting another potential combination strategy for WM therapy. MULTIPLE MYELOMA
Tai et al.39 demonstrated that ibrutinib blocked multiple myeloma (MM) cell growth and survival triggered by interleukin6 or co-culture with bone marrow stromal cells in vitro, and also significantly inhibited MM cell growth in vivo. Rushworth et al.40 showed that ibrutinib was cytotoxic to patient-derived MM cells and that ibrutinib significantly augmented the activities of bortezomib and lenalidomide in MM cells. The studies suggest that ibrutinib has activity against MM and can be combined with proteasome inhibitors or lenalidomide for MM treatment. HAIRY CELL LEUKEMIA
Sivina et al.41 reported that ibrutinib inhibited BCR signaling and chemokine (CCL3 and CCL4) secretion, and inhibited growth and proliferation of hairy cell leukemia cell lines and viability of primary hairy cell leukemia cells. These results suggest that ibrutinib might also be used to treat this particular type of B-cell malignancy. ACUTE LYMPHOBLASTIC LEUKEMIA AND ACUTE MYELOBLASTIC LEUKEMIA
Kim et al.42 reported at the ASH 2012 meeting that ibrutinib interfered with B-cell acute lymphoblastic leukemia (ALL) cell proliferation and survival.42 Interestingly, ibrutinib also appears to have activity against acute myeloblastic leukemia (AML), first reported by Rushworth et al.,43 who found that ibrutinib VOLUME 97 NUMBER 5 | MAY 2015 | www.wileyonlinelibrary/cpt
inhibited blast proliferation of primary human AML cells and that ibrutinib significantly augmented cytotoxic activities of cytarabine and daunorubicin in AML. However, at the ASH 2014 meeting, Rotin et al.44 reported that ibrutinib lacked singleagent activity in AML, although it sensitized TEX and OCIAML2 cell lines and primary AML cells to some reactive oxygen species-inducing agents, including daunorubicin. CLINICAL STUDIES
The first phase 1 clinical trial evaluating the safety and efficacy of ibrutinib in B-cell malignancy enrolled 56 patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL), and NHL.45 Patients received escalating doses of ibrutinib under either 28 days on/7 days off (1.25–12.5 mg/kg) or once-daily continuous (8.3 mg/kg or 560 mg) dosing schedules. Ibrutinib was rapidly absorbed and eliminated after oral administration. Mean peak plasma concentrations were reached between one and two hours. The initial half-life was approximately two to three hours, and the mean apparent terminal half-life ranged from four to six hours. The maximum-tolerated dose was not reached. Most common adverse events (AEs) observed were typically grade 1 or 2 in severity, with no evidence of cumulative toxicity with prolonged dosing. A daily dose of 2.5 mg/kg was sufficient to achieve complete and durable inhibition of Btk throughout the entire treatment cycle. Of the 50 patients evaluable for tumor response, the objective response rate was 60% (complete response [CR] rate 5 16%; partial response [PR] rate 5 44%). Responses were observed in 7 of 9 patients with MCL (3 CR), 3 of 4 patients with WM, 11 of 16 patients with CLL/SLL (2 CR), 6 of 16 patients with follicular lymphoma (FL; 3 CR), 2 of 7 patients with DLBCL, and 1 of 4 patients with marginal zone lymphoma (MZL). The response was durable, with a median progression-free survival (PFS) of 13.6 months for all patients at the time of data cutoff. The encouraging results from this trial prompted clinical studies of ibrutinib in various individual types of B-cell malignancies, particularly CLL/SLL and MCL. Published data on clinical trials are summarized in Table 1, and unpublished clinical studies with data available are summarized in Table 2. Information on more clinical trials is available in Supplementary Table S1 online. CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA Ibrutinib monotherapy in CLL/SLL
A multicenter, phase 1b/2 trial enrolled 85 patients with relapsed or refractory CLL/SLL, and ibrutinib was administered at 420 mg (51 patients) or 840 mg (34 patients) fixed daily dose.46 The overall response rates were 71% in both groups, and an additional 20% and 15% of patients in the respective groups had nodal response with lymphocytosis. The response was durable and independent of Rai stage before treatment, number of previous chemotherapies, and 17p13.1 or 11q22.3 deletion, but patients with unmutated IGHV had a higher response rate (77%) compared with patients bearing IGHV mutation (33%). The estimated 26-month PFS and overall survival (OS) rates were 75% and 83%, respectively. Of note, patients with 17p13.1 deletion had lower 26-month PFS (57%) and OS rates (70%). An updated CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
analysis of this study was presented at the ASH 2013 meeting.47 Results from this study led to accelerated FDA approval of ibrutinib in February of 2014 for treatment of patients with CLL who have received at least one prior therapy. An open-label, multicenter, phase 1b/2 trial enrolled 31 patients who were at least 65 years old and had untreated CLL/ SLL.48 Although two cohorts (420 mg or 840 mg daily dose) were initially planned, the high-dose cohort was soon closed when comparable activity of the doses was shown in relapsed or refractory patients with CLL/SLL.46 Eventually, 27 patients received 420 mg and 4 patients received 840 mg daily doses. Analysis was based on pooled data because results for the two dose cohorts were similar. The median follow-up was 22.1 months. Objective response was observed in 22 of 31 patients (71%), with 4 achieving complete response (13%), 17 with PR (55%), and 1 with nodular PR (3%). In addition, 4 patients (13%) achieved a PR with lymphocytosis (PRL) and 3 (10%) had stable disease. Response was independent of Rai stage, 17p13.1 or 11q22.3 deletion, and IGHV mutation status. The 24-month PFS and OS rates were 96.3% and 96.6%, respectively. Median PFS was not reached. Response was durable in the above studies, and the median duration of response (DOR) was not yet reached after a median follow-up of 27.2 months.47 Interim results of another single center phase 2 trial of single agent ibrutinib in CLL was reported at the ASH 2013 meeting.49 The first cohort included patients with 17p deletion, and the second cohort included patients 65 years or older without 17p deletion. At 6 months, 53% of 21 patients in the 17p deletion cohort achieved PR (an additional 43% of patients achieved PRL), and 81% of 26 patients in the elderly cohort had PR (an additional 9% of patients had PRL). The difference was probably because of slower clearance of treatment-induced lymphocytosis in patients with 17p deletion. The estimated event-free survival rate for the entire population at 14 months was 93%. These results were comparable to those previously published.46,48 The efficacy of ibrutinib in patients who had relapsed or refractory CLL/SLL with 17p deletion is under investigation in a phase 2 trial (RESONATE-17), the interim results of which were presented at the ASH 2014 meeting.50 One hundred thirty-seven patients with CLL and seven with SLL were included in this analysis, with a median age of 64 years and a median of two prior therapies. Investigator-assessed overall response rate (ORR) was 82.6%, including 17.4% PRL. At a median follow-up of 13.0 months (range 5 0.5–16.7 months), the median PFS and DOR had not been reached. At 12 months, 79.3% of patients were alive and progression-free. These results suggest that ibrutinib remains an effective therapy for patients with CLL/SLL with 17p deletion, a traditional high-risk factor. Ibrutinib compared with other single agents for CLL/SLL
A multicenter, open-label, phase 3 study (RESONATE) compared ibrutinib vs. ofatumumab in patients with relapsed or refractory CLL or SLL.51 Three hundred ninety-one patients were randomized into the oral ibrutinib group (420 mg daily; n 5 195) or the intravenous ofatumumab group (300 mg at week 1, 2000 mg weekly for 7 weeks, and then every 4 weeks for 16 weeks; n 5 196). The ORR was significantly higher in the 459
Table 1 Published clinical trials of ibrutinib Study
Phase
Disease type
No. of patients
Regimen
Outcome
Advani (2013)45
1
NHL (R/R)
56
Ibrutinib
ORR 60% (CR 16%, PR 44%) (50 patients evaluable for response) Response seen: CLL/SLL: 11/16 (2 CR) MCL: 7/9 (3 CR) DLBCL: 2/7 FL: 6/16 (3 CR) WM: 3/4 MZL: 1/4 Median PFS 13.6 mo
Wang (2013)58
2
MCL (R/R)
111
Ibrutinib
ORR 68% (CR 21%, PR 47%) Median PFS 13.9 mo 18-mo OS 58%
Byrd (2013)46
1b/2
CLL/SLL (R/R)
85
Ibrutinib
ORR 71% (CR 2%, PR 68%), PRL 18% 26-mo PFS 75% 26-mo OS 83%
O’Brien (2014)48
1b/2
CLL/SLL (untreated)
31
Ibrutinib
ORR 71% (CR 13%, PR 55%, nPR 3%), PRL 13% 24-mo PFS 96.3% 24-mo OS 96.6%
Byrd (2014)51
3
CLL/SLL (R/R)
391
Ibrutinib (n 5 195) vs. ofatumumab (n 5 196)
ORR 42.6%, PRL 20% 6-mo PFS 88% 12-mo OS 90%
Burger (2014)53
2
CLL/SLL (high risk)
40
Ibrutinib plus rituximab
ORR 95% (CR 8%, PR 87%) (46 patients evaluable for response) 18-mo PFS 78.0% 18-mo OS 83.8%
Younes (2014)65
1b
NHL (untreated)
33
Ibrutinib plus R-CHOP
ORR 94% (CR 72%, PR 22%) (32 patients received R-CHOP) Response seen: DLBCL: 22/23
Maddocks (2014)66
1/1b
NHL (untreated)
48
Ibrutinib plus rituximab and bendamustine
ORR 72% (CR 52%, PR 20%) (46 patients evaluable for response) Response seen: MCL: 16/17 (13 CR) DLBCL: 6/16 (5 CR) FL: 9/10 (5 CR) MZL: 1/1 Transformed: 1/2 (1 CR) 2-y PFS 50.3% 2-y OS 56.5%
CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin’s lymphoma; nPR, nodular partial response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial €m’s macroglobulinemia. response; PRL, partial response with lymphocytosis; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma; WM, Waldenstro
ibrutinib group (42.6%) than in the ofatumumab group (4.1%). An additional 20% of patients in the ibrutinib group achieved PRL. At a median follow-up of 9.4 months, ibrutinib significantly prolonged the duration of PFS compared to ofatumumab (not reached vs. 8.1 months; hazard ratio 5 0.22; 95% confidence interval 5 0.15–0.32; P < 0.001). The 6-month PFS rate was 88% in the ibrutinib group and 65% in the ofatumumab group. Ibrutinib also significantly increased the OS rate when compared with ofatumumab, with a 12-month OS rate of 90% vs. 81% (hazard ratio 5 0.43; 95% confidence interval 5 0.24–0.79; P 5 0.005). Of note, the survival benefits of ibrutinib were achieved regardless of 17p13.1 deletion status or resistance to purine analogues. An updated analysis of this study was presented 460
at the ASH 2014 meeting.52 Based on the results from this study, the FDA approved ibrutinib for use in patients with CLL with 17p deletion in July of 2014. A phase 3 study of ibrutinib vs. rituximab in relapsed or refractory CLL/SLL, and another randomized, multicenter, open-label, phase 3 trial studying ibrutinib vs. chlorambucil in elderly patients with untreated CLL/SLL (RESONATE-2) are ongoing. Ibrutinib in combination with chemoimmunotherapy for CLL/ SLL
Combination of ibrutinib with CD-20 antibodies has been investigated in multiple clinical trials. A single-arm phase 2 study evaluated the combination of ibrutinib and rituximab in patients VOLUME 97 NUMBER 5 | MAY 2015 | www.wileyonlinelibrary/cpt
Table 2 Partially reported ongoing clinical trials of ibrutinib Study
Phase
Disease type
No. of patients
Regimen
Outcome
Farooqui (2013)
2
CLL/SLL (elderly, or with 17p deletion)
53
Ibrutinib
PR 66%, PRL 28% 17p deletion cohort (n 5 21): PR 53%, PRL 43% Elderly (65) cohort (n 5 26): PR 81%, PRL 9% 14-mo EFS 93%
O’Brien (2014)50
2
CLL/SLL (R/R, with 17p deletion)
144
Ibrutinib
ORR 82.6% (including 17.4% PRL) 12-mo PFS 79.3%
Jaglowski (2014)54
1b/2
CLL/SLL (R/R)
71
Ibrutinib plus ofatumumab
ORR 71–100% 12-mo PFS 85–90%
Sharman (2014)55
2
CLL and MCL (R/R)
33 CLL 7 MCL
Ibrutinib plus ublituximab
CLL (n 5 18): ORR 94% (CR 5.5%) MCL (n 5 6): ORR 83% (CR 50%)
Brown (2013)56
1b
CLL/SLL (R/R)
30
Ibrutinib plus bendamustine and rituximab
ORR 93% (CR 17%, PR 67%, nPR 10%), PRL 3% 12-mo PFS 90%
Pollyea (2014)57
1
CLL/SLL (R/R)
11
Ibrutinib plus lenalidomide
PR 100% (9 patients evaluable for response)
Wang (2014)60
2
MCL (progressed after lenalidomide)
120
Ibrutinib
ORR 62.7% (CR 20.9%) Median PFS 10.5 mo 18-mo OS 61%
Wang (2014)61
2
MCL (R/R)
50
Ibrutinib plus rituximab
ORR 87% (CR 38%, PR 49%) (45 patients evaluable for response)
Wilson (2012)62
2
DLBCL (R/R)
70
Ibrutinib
ABC subtype (n 5 25): ORR 40% (CR 8%, PR 32%) 1 PR in GCB subtype (n 5 19) No response in unclassified (n 5 13)
Fowler (2012)63
1
FL (R/R)
16
Ibrutinib
ORR 54.5% (CR 27.3%, PR 27.3%) (11 patients evaluable for response) Median PFS 13.4 mo
Bartlett (2014)64
2
FL (R/R)
40
Ibrutinib
ORR 30% (CR 2.5%, PR 27.5%) Median PFS 9.9 mo
Christian (2014)67
1
NHL (R/R)
13
Ibrutinib plus lenalidomide
CR in 2 of 4 patients with DLBCL PR in 1 MCL and 1 transformed FL
Treon (2013)68
2
WM (R/R)
63
Ibrutinib
Best ORR (MR or better) 81% (4 VGPR, 32 PR, 15 MR) Major response rate (PR or better) 57.1%
Vij (2014)69
2
MM (R/R)
69
Ibrutinib 6 dexamethasone
Best response seen with higher dose ibrutinib plus dexamethasone (n 5 20): 1 PR, 4 MR
Jones (2014)70
2
HCL
8
Ibrutinib
Marrow clearance seen in first patient undergoing evaluation
49
ABC, activated B-cell-like; CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; FL, follicular lymphoma; GCB, germinal center B-cell-like; HCL, hairy cell leukemia; MCL, mantle cell lymphoma; MR, minor response; NHL, non-Hodgkin’s lymphoma; nPR, nodular partial response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PRL, partial response with lymphocytosis; R/R, relapsed or €m’s macroglobulinemia. refractory; SLL, small lymphocytic lymphoma; VGPR, very good partial response; WM, Waldenstro
with CLL with high-risk features.53 Forty patients were enrolled, among whom 20 had 17p deletion or TP53 mutation (16 previously treated, 4 untreated), 13 had disease relapse with 11q deletion, and 7 had PFS less than 36 months after first-line chemoimmunotherapy. Treatment consisted of oral ibrutinib (420 mg daily in 28-day cycles continuously) and intravenous rituximab (375 mg/m2 weekly during cycle 1, and once every 4 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
weeks until cycle 6). At a median follow-up of 16.8 months, 37 of the 39 patients (95%) evaluable for response assessment achieved complete (3; 8%) or partial (34; 87%) remission. Median DOR was 15.44 months. The 18-month PFS and OS rates were 78.0% and 83.8%, respectively, for all 40 patients. In the 20 patients with 17p deletion or TP53 mutation, the PFS and OS rates were 72.4% and 78.4%, respectively, which did not 461
differ significantly from those in patients without these genetic alterations (P 5 0.412 and 0.235 for PFS and OS, respectively). Of note, fewer patients in this study had persistent lymphocytosis than with ibrutinib single-agent treatment seen in other trials, suggesting that CD20 antibody may alleviate ibrutinib-induced lymphocytosis. Combination of ibrutinib with the second generation CD20 antibody ofatumumab for relapsed or refractory CLL/SLL and related diseases (prolymphocytic leukemia, Richter’s transformation) is being studied in a phase 1b/2 trial, and the interim results were reported at the ASCO 2014 meeting.54 Seventy-one patients were treated with ibrutinib (420 mg daily in 28-day cycles continuously) and ofatumumab (300/2000 mg, weekly 3 8 and then monthly 3 4) in three different administration sequences. Group 1 patients received ofatumumab starting with cycle 2; group 2 patients received concurrent treatment starting with cycle 1; and group 3 patients received ibrutinib starting with cycle 3. ORR in CLL/SLL was 100% in group 1, 79% in group 2, and 71% in group 3. At 12 months, PFS rates were 89%, 85%, and 90% in groups 1, 2, and 3, respectively. Combination of ibrutinib with the novel third generation CD20 antibody ublituximab for relapsed or refractory CLL and MCL is being studied in a phase 2 trial, and the interim results were reported at the ASH 2014 meeting.55 Thirty-three patients with CLL and seven patients with MCL have been enrolled to date, who received ibrutinib (420 mg for CLL, 560 mg for MCL, continuously) and ublituximab (600 or 900 mg for CLL, 900 mg for MCL, days 1, 8, and 15 in cycle 1 and day 1 in cycles 2–6) concurrently. At the time of report, 24 of 40 patients were evaluable for response. ORR was 94% for CLL (18 patients, 5.5% CR) and 83% for MCL (6 patients, 50% CR). Consistent with the effect seen with ibrutinib and rituximab combination,53 addition of ublituximab seemed to mitigate ibrutinib-related lymphocytosis seen with ibrutinib monotherapy. Collectively, the above data strongly suggest that ibrutinib in combination with CD20 antibodies is a very promising strategy to treat patients with relapsed or refractory CLL/SLL. How this combination compares with chemoimmunotherapy as frontline therapy is currently being studied. In a few ongoing clinical trials, the ibrutinib and rituximab combination will be compared with FCR or bendamustine plus rituximab (BR), and ibrutinib plus ofatumumab will be compared with chlorambucil plus ofatumumab. Combination of ibrutinib with chemoimmunotherapy is under investigation in CLL/SLL as well. A phase 1b trial studied the combination of ibrutinib with BR for the treatment of relapsed or refractory CLL/SLL, and the final results were reported at the ASH 2013 meeting.56 Thirty patients were enrolled, with a median age of 62 years and a median of two prior therapies. Treatment consisted of ibrutinib (420 mg daily), bendamustine (70 mg/m2 on days 1–2 of cycle 1 and day 1 of cycles 2–6), and rituximab (375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2–6). With a median treatment duration of 16 months, the ORR was 93% (5 CRs, 20 PRs, and 3 nodular PRs), and one additional patient (3%) achieved PRL. The responses were independent of high-risk features. The estimated 12-month 462
PFS rate was 90%. These encouraging results prompted a phase 3 study (HELIOS), which is currently ongoing. The combination of ibrutinib with FCR is being studied for untreated younger patients with CLL in a phase 2 trial (iFCR). These studies will further define the benefits of adding ibrutinib to chemoimmunotherapy in CLL/SLL. Combination of ibrutinib with lenalidomide for CLL is also under investigation. Interim results of an ongoing phase 1 trial were reported at the ASH 2014 meeting.57 Eleven patients with relapsed or refractory CLL/SLL were enrolled to date. Ibrutinib was given continuously at a fixed 420 mg daily dose. Lenalidomide was given starting from the second month (cycle 1) for 12 monthly cycles, with four dose escalation cohorts (2.5, 5, 7.5, and 10 mg) planned. At the time of report, nine patients were evaluable, with a median of eight treatment cycles completed. The ORR was 100% (all PRs). All nine patients remained alive with a median follow-up of 263 days. The response rate was exceptionally high, although further data are needed to evaluate this potentially powerful combination strategy. Further addition of rituximab to the ibrutinib and lenalidomide combination is being studied in relapsed or refractory CLL/SLL. MANTLE CELL LYMPHOMA Single agent ibrutinib in relapsed or refractory MCL
A phase 2 trial enrolled 111 patients with relapsed or refractory MCL, with a median age of 68 years and a median of three prior therapies.58 Ibrutinib was administered orally at a 560 mg daily dose. After an estimated median follow-up of 15.3 months, the ORR was 68%, with a CR rate of 21% and a PR rate of 47%. The response was independent of prior treatment with bortezomib (2 cycles vs.
B-cell receptor (BCR) signaling pathway is imperative for cellular selection, development, maturation, and survival of normal Bcells. Bruton’s tyrosine kinase (Btk) is a key kinase downstream of the B-cell receptor that is critical to the BCR signaling. Lack of Btk function leads to the development of X-linked agammaglobulinemia (XLA), which is characterized by deficiency of mature B-cell and antibody production and recurrent infections. In recent years, upregulated BCR signaling has been recognized as an important pathogenesis mechanism in B-cell malignancies. Small molecule inhibitors targeting key kinases in the BCR pathway, in particular Btk, have been developed and are under investigation in both preclinical and clinical studies. By far, the most well studied agent is ibrutinib, formerly known as PCI-32765, a covalent, irreversible inhibitor of Btk. In preclinical studies, it has been shown to have activity against a variety of B-cell malignancies in cell lines, patient samples, and animal models. In clinical studies, ibrutinib is well-tolerated and has shown great efficacy in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and some other types of non-Hodgkin’s lymphoma (NHL). Furthermore, ibrutinib has gained US Food and Drug Administration (FDA) approval for use in patients with CLL and MCL who have received at least one prior therapy, and in patients with CLL with 17p deletion. Many clinical studies are ongoing to further evaluate the safety and efficacy of ibrutinib in
B-cell malignancies, as a single agent or in combination with chemoimmunotherapy or other small molecule signal transduction inhibitors. In this review, we provide a brief overview of the BCR pathway and Btk, and summarize available preclinical and clinical data on the first-in-class Btk inhibitor ibrutinib in B-cell malignancy. B-CELL RECEPTOR SIGNALING PATHWAY
The BCR signaling pathway is critical to the development and maturation of B-cells. A simplified diagram of this pathway is shown in Figure 1 and described below.1,2 The membrane-bound BCR associates with heterodimeric CD79a and CD79b proteins, which contain immunoreceptor tyrosine-based activation motifs that are crucial for BCR signaling initiation. After BCR aggregation, immunoreceptor tyrosine-based activation motifs are phosphorylated primarily by Src-family tyrosine kinases, such as Lyn. Phosphorylated immunoreceptor tyrosine-based activation motifs serve as a scaffolding platform for engaging and activating SH2 domains containing kinases, including Syk. The BCR co-receptor CD19 is also phosphorylated by Lyn upon BCR ligation, and phosphorylated CD19 recruits the SH2 domain containing kinase phosphatidylinositol-3-kinase (PI3K). Active PI3K phosphorylates the plasma membrane lipid phosphatidylinositol 4, 5-bisphosphate to generate phosphoinositide phosphatidylinositol-3, 4, 5-trisphosphate, which is essential
1 Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA; 2Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 3Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Correspondence: ML Wang ([email protected])
Received 1 December 2014; accepted 28 January 2015; advance online publication 2 February 2015. doi:10.1002/cpt.85 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
455
Figure 1 B-cell receptor (BCR) pathway.
for recruitment of the Btk through its pleckstrin homology domain. In addition, activated Syk phosphorylates the B-cell linker protein BLNK, which is directly recruited to BCR through its interaction with CD79a. Phosphorylated BLNK associates with both Btk and phospholipase g2 (PLCg2) through their SH2 domains, and Btk is then phosphorylated and activated by Syk, while PLCg2 is dually phosphorylated and activated by Syk and Btk. Activated PLCg2 cleaves phosphatidylinositol 4, 5-bisphosphate and generates inositol triphosphate and diacylglycerol. Inositol triphosphate generation causes calcium mobilization from both intracellular stores and extracellular influx, and Ca21 together with diacylglycerol then activates PKCb, which, in turn, phosphorylates a variety of downstream substrates and activates multiple signaling pathways. Importantly, IjB kinase is activated 456
downstream of PKCb, leading to IjB phosphorylation and dissociation of a key transcription factor NF-jB, which translocates into the nucleus and mediates transcriptional regulation of many genes. In addition, Ca21 in conjunction with calmodulin also activates another transcription factor nuclear factor of activated T-cells, which also regulates expression of a variety of genes. BRUTON’S TYROSINE KINASE
Among the many kinases involved in BCR signaling, Btk is a key molecule that is critical to normal B-cell development. Its essential role is demonstrated in the inherited syndrome XLA, which was initially described by Dr. Ogden Carr Bruton in 1952.3 XLA is a human immunodeficiency syndrome characterized by failure of pre-B-cells in the bone marrow to develop into circulating mature B-cells. This VOLUME 97 NUMBER 5 | MAY 2015 | www.wileyonlinelibrary/cpt
of eight dogs with NHL (follicular large cell and diffuse immunoblastic types).10 Subsequent preclinical studies demonstrated that ibrutinib was active in a variety of B-cell malignancies including CLL, MCL, diffuse large B-cell lymphoma (DLBCL), and Waldenstr€om’s macroglobulinemia (WM). CHRONIC LYMPHOCYTIC LEUKEMIA
Figure 2 Ibrutinib binds to the ATP-binding site of Bruton’s tyrosine kinase (Btk). Domain structure of Btk (a) and chemical structure of ibrutinib (b).
disorder is caused by a single gene defect of Btk on X chromosome.4 This remarkable association of Btk with the pathogenesis of XLA supports its critical role as a key regulator of B-cell development. Btk contains five domains: a pleckstrin homology domain; a Tec homology domain, which includes the Btk homology, and polyproline region domains; two Src homology domains (SH2 and SH3); and a tyrosine kinase domain (Figure 2). These domains can recognize various signaling molecules, allowing Btk to function in the center of the BCR signaling pathway. TARGETING BTK IN B-CELL MALIGNANCIES
The BCR signaling pathway is implicated in the pathogenesis of B-cell malignancies, including CLL and NHL.5–8 The essential role of Btk in the BCR pathway and B-cell survival, demonstrated in the pathogenesis of XLA, makes it an attractive therapeutic target for B-cell malignancies. A number of Btk inhibitors have been developed, among which ibrutinib (Figure 2), formerly known as PCI-32765, is by far the most well studied agent in both preclinical and clinical settings. Ibrutinib (Imbruvica) is a first-in-class Btk inhibitor, manufactured by Pharmacyclics (Sunnyvale, CA) and co-developed in partnership with Janssen Pharmaceuticals (Beerse, Belgium)/Johnson & Johnson (New Brunswick, NJ). Like other Btk inhibitors, ibrutinib was designed to inhibit Btk by selectively interacting with an ATP-binding site in the tyrosine kinase domain, thereby preventing Btk phosphorylation and activation. Specifically, it irreversibly binds to Cys-481 in the active site of Btk (Figure 2), resulting in its sustained inhibition. Ibrutinib is available orally, and is characterized by its high potency with an IC50 of 0.5 nM, and high selectivity toward Btk over other kinases.9 Many preclinical and clinical studies have demonstrated its great promise in the treatment of various B-cell malignancies. PRECLINICAL STUDIES
The efficacy of ibrutinib in B-cell malignancies was first established in spontaneous canine lymphoma models. Daily oral administration of ibrutinib resulted in partial response in three CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
A number of elegant preclinical studies have demonstrated the activity of ibrutinib against CLL. Herman et al.11 first showed that ibrutinib induced apoptosis and inhibited activationinduced proliferation of CLL cells in vitro. Ponader et al.12 reported that ibrutinib inhibited CLL cell survival and migration in response to homing chemokines, and downregulated secretion of BCR-dependent chemokines by CLL cells. Importantly, they demonstrated that ibrutinib profoundly inhibited CLL progression in an adoptive transfer TCL1 mouse model of CLL. Woyach et al.13 demonstrated that ibrutinib inhibited the development of CLL and improved survival in TCL1 transgenic mice, and improved overall survival of CB17/SCID mice transplanted with TCL1 leukemic spleen lymphocytes. Herman et al.14 showed that ibrutinib decreased proliferation and induced apoptosis of CLL cells, and reduced tumor burden in the NOD/ scid/gcnull mouse xenograft model. Potential ibrutinib-containing combination therapy for CLL has also been studied preclinically. Promising candidates to combine with ibrutinib included proteasome inhibitors,15 Bcl-2 inhibitors,16 and IRAK1/4 kinase inhibitors.17 These combinations were somewhat better studied in other B-cell malignancies and are described below. In addition, Wu et al.18 reported at the ASH 2014 meeting that whereas ibrutinib and Wnt signaling inhibitor dimethyl fumarate both had single-agent activity against CLL in patient-derived tumor cells and Rag22/2gc2/2 mice engrafted with human CLL cells, the combination achieved higher therapeutic efficacy. MANTLE CELL LYMPHOMA
Ponader et al.19 first reported at the ASH 2011 meeting that ibrutinib was effective in inhibiting proliferation of MCL cell lines, most prominently JVM-2 and Mino. They also showed that ibrutinib inhibited IgM-stimulated secretion of chemokines CCL3 and CCL4 by MCL cell lines. Ou et al.20 also reported single-agent activity of ibrutinib against a variety of MCL cell lines at the same meeting. Cinar et al.21 showed that ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration-dependent and time-dependent manners, and induced a concentration-dependent apoptosis in both cell lines. At the ASH 2013 meeting, Ou et al.22 reported that, in an huSCID MCL mouse model, ibrutinib mobilized MCL cells from the lymphoid tissue into peripheral blood, leading to MCL cytotoxicity and increased mouse survival. A number of preclinical studies have explored potential ibrutinib-containing combination strategy for MCL therapy, with proteasome inhibitors and Bcl-2 inhibitors being the most studied candidates. Brett et al.15 reported at the ASH 2013 meeting that a combination of ibrutinib with proteasome inhibitors carfilzomib and bortezomib, as well as Bcl-2 inhibitor ABT-199, 457
displayed robust synergistic cytotoxicity toward MCL cell lines. The synergistic effect between ibrutinib and carfilzomib was also seen in samples from patients with MCL and CLL.15 Consistent with these findings, Dasmahapatra et al.23 demonstrated that coadministration of ibrutinib and bortezomib synergistically increased apoptosis of MCL cells. The same combination strategy was also effective against both activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtype of DLBCL cells.23 Zhao et al.24 also demonstrated that the ibrutinib and ABT-199 combination displayed strong synergistic effects in MCL cell lines as well as primary cells from patients with recurrent MCL. Portell et al.16 reported, again at the ASH 2014 meeting, the synergistic effect of ibrutinib and carfilzomib or ABT-199 on apoptosis of circulating tumor cells from patients with MCL. Abundant data, as described above, support that the combination of ibrutinib with proteasome inhibitors or Bcl-2 inhibitors makes a promising therapeutic strategy for MCL. Another promising combination strategy is ibrutinib plus CD20 antibodies. At the ASH 2014 meeting, Zhang et al.25 demonstrated that the ibrutinib and rituximab combination synergistically induced apoptosis of MCL cell lines and primary MCL cells, and eradicated MCL cells and prolonged animal survival in the hu-SCID MCL mouse model. Other combination strategies are also being explored. At the ASH 2012 meeting, Sahakian et al.26 reported that, although ibrutinib and HDAC6 inhibitor ACY1215 both decreased viability of MCL cell lines in vitro, the combination resulted in a threefold increase in apoptosis induction. Synergistic effect between ibrutinib and another HDAC inhibitor, vorinostat, in inducing apoptosis and growth inhibition was reported at the ASH 2014 meeting by Hagiwara et al.27 Tabe et al.28 showed at the ASH 2014 meeting that the combination of ibrutinib with KPT-330, a selective inhibitor of nuclear export, synergistically inhibited cyclin D1 expression and reduced tumor cell proliferation. DIFFUSE LARGE B-CELL LYMPHOMA
Davis et al.8 first showed activity of ibrutinib against ABC subtype of DLBCL with chronic active BCR signaling. Consistently, Zoellner et al.29 reported at the ASH 2011 meeting that ibrutinib reduced cell growth in ABC but not GCB DLBCL cell lines. A number of preclinical studies of combining ibrutinib with other agents, including PI3K inhibitor, Syk inhibitor, mTOR inhibitor, Bcl-2 inhibitor, and lenalidomide, have been conducted in DLBCL with promising results reported. Combination of ibrutinib with either mTOR inhibitor temsirolimus or PI3K inhibitor Cal101 showed additive effect in ABC and synergistic effect in GCB DLBCL cell lines.29 Ezell et al.30 found that the combination of ibrutinib with AZD2014, an mTOR catalytic inhibitor, were highly synergistic in killing the ABC subtype of DLBCL cell lines. This combination induced apoptosis both in vitro and in vivo, and resulted in tumor regression in the OCI-LY10 xenograft model. Kuo et al.31 reported at the ASH 2014 meeting that the combination of ibrutinib and Bcl-2 inhibitors completely inhibited tumor growth in murine models of ABC DLBCL, and Bcl-2 or Syk inhibitors resensitized ibrutinib-resistant cells. Yang et al.32 reported that ibrutinib synergized with lenalidomide in killing ABC DLBCL cells both in vitro and in the OCI-LY10 xenograft 458
model. In a recent unbiased screening, ibrutinib was also shown to interact favorably with PI3K-Akt-mTOR signaling inhibitors, other BCR signaling inhibitors, Bcl-2 family inhibitors, and certain chemotherapy agents in ABC DLBCL.33 Although most available data were on ABC DLBCL, use of ibrutinib might be potentially extended to other subtypes of DLBCL as well. In GCB DLBCL cell lines, Zheng et al.34 showed that ibrutinib inhibited proliferation, induced apoptosis, and attenuated production of the CCL3 and CCL4 chemokines. In double-hit DLBCL, the combination of ibrutinib and carfilzomib synergistically inhibited cell proliferation and induced cell death in three double-hit DLBCL cell lines (CJ, RC, and U-2973).35 This finding provides promise to the therapy of double-hit DLBCL, which is notoriously resistant to chemotherapies. € WALDENSTROM’S MACROGLOBULINEMIA
The L265P mutation of MYD88, an adapter that promotes Tolllike receptor and interleukin-1 receptor signaling through the IRAK1/4/TRAF6/NF-jB pathway, was reported in over 90% of patients with WM. At the ASH 2014 meeting, Yang et al.36 reported that the L265P mutant induced robust Btk phosphorylation in WM cells, and ibrutinib treatment resulted in significant WM tumor cell killing, and ibrutinib was synergistic with an IRAK1/4 kinase inhibitor in killing WM cells. This combination was also shown to be effective in ABC DLBCL and CLL with MYD88 L265P mutation, which occurred in 30% and 6.25% of patients, respectively.17,37 Chitta et al.38 reported at the ASH 2014 meeting that the Bcl-2 inhibitor ABT-199 resensitized and synergized with ibrutinib in ibrutinib-resistant WM cells, suggesting another potential combination strategy for WM therapy. MULTIPLE MYELOMA
Tai et al.39 demonstrated that ibrutinib blocked multiple myeloma (MM) cell growth and survival triggered by interleukin6 or co-culture with bone marrow stromal cells in vitro, and also significantly inhibited MM cell growth in vivo. Rushworth et al.40 showed that ibrutinib was cytotoxic to patient-derived MM cells and that ibrutinib significantly augmented the activities of bortezomib and lenalidomide in MM cells. The studies suggest that ibrutinib has activity against MM and can be combined with proteasome inhibitors or lenalidomide for MM treatment. HAIRY CELL LEUKEMIA
Sivina et al.41 reported that ibrutinib inhibited BCR signaling and chemokine (CCL3 and CCL4) secretion, and inhibited growth and proliferation of hairy cell leukemia cell lines and viability of primary hairy cell leukemia cells. These results suggest that ibrutinib might also be used to treat this particular type of B-cell malignancy. ACUTE LYMPHOBLASTIC LEUKEMIA AND ACUTE MYELOBLASTIC LEUKEMIA
Kim et al.42 reported at the ASH 2012 meeting that ibrutinib interfered with B-cell acute lymphoblastic leukemia (ALL) cell proliferation and survival.42 Interestingly, ibrutinib also appears to have activity against acute myeloblastic leukemia (AML), first reported by Rushworth et al.,43 who found that ibrutinib VOLUME 97 NUMBER 5 | MAY 2015 | www.wileyonlinelibrary/cpt
inhibited blast proliferation of primary human AML cells and that ibrutinib significantly augmented cytotoxic activities of cytarabine and daunorubicin in AML. However, at the ASH 2014 meeting, Rotin et al.44 reported that ibrutinib lacked singleagent activity in AML, although it sensitized TEX and OCIAML2 cell lines and primary AML cells to some reactive oxygen species-inducing agents, including daunorubicin. CLINICAL STUDIES
The first phase 1 clinical trial evaluating the safety and efficacy of ibrutinib in B-cell malignancy enrolled 56 patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL), and NHL.45 Patients received escalating doses of ibrutinib under either 28 days on/7 days off (1.25–12.5 mg/kg) or once-daily continuous (8.3 mg/kg or 560 mg) dosing schedules. Ibrutinib was rapidly absorbed and eliminated after oral administration. Mean peak plasma concentrations were reached between one and two hours. The initial half-life was approximately two to three hours, and the mean apparent terminal half-life ranged from four to six hours. The maximum-tolerated dose was not reached. Most common adverse events (AEs) observed were typically grade 1 or 2 in severity, with no evidence of cumulative toxicity with prolonged dosing. A daily dose of 2.5 mg/kg was sufficient to achieve complete and durable inhibition of Btk throughout the entire treatment cycle. Of the 50 patients evaluable for tumor response, the objective response rate was 60% (complete response [CR] rate 5 16%; partial response [PR] rate 5 44%). Responses were observed in 7 of 9 patients with MCL (3 CR), 3 of 4 patients with WM, 11 of 16 patients with CLL/SLL (2 CR), 6 of 16 patients with follicular lymphoma (FL; 3 CR), 2 of 7 patients with DLBCL, and 1 of 4 patients with marginal zone lymphoma (MZL). The response was durable, with a median progression-free survival (PFS) of 13.6 months for all patients at the time of data cutoff. The encouraging results from this trial prompted clinical studies of ibrutinib in various individual types of B-cell malignancies, particularly CLL/SLL and MCL. Published data on clinical trials are summarized in Table 1, and unpublished clinical studies with data available are summarized in Table 2. Information on more clinical trials is available in Supplementary Table S1 online. CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA Ibrutinib monotherapy in CLL/SLL
A multicenter, phase 1b/2 trial enrolled 85 patients with relapsed or refractory CLL/SLL, and ibrutinib was administered at 420 mg (51 patients) or 840 mg (34 patients) fixed daily dose.46 The overall response rates were 71% in both groups, and an additional 20% and 15% of patients in the respective groups had nodal response with lymphocytosis. The response was durable and independent of Rai stage before treatment, number of previous chemotherapies, and 17p13.1 or 11q22.3 deletion, but patients with unmutated IGHV had a higher response rate (77%) compared with patients bearing IGHV mutation (33%). The estimated 26-month PFS and overall survival (OS) rates were 75% and 83%, respectively. Of note, patients with 17p13.1 deletion had lower 26-month PFS (57%) and OS rates (70%). An updated CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
analysis of this study was presented at the ASH 2013 meeting.47 Results from this study led to accelerated FDA approval of ibrutinib in February of 2014 for treatment of patients with CLL who have received at least one prior therapy. An open-label, multicenter, phase 1b/2 trial enrolled 31 patients who were at least 65 years old and had untreated CLL/ SLL.48 Although two cohorts (420 mg or 840 mg daily dose) were initially planned, the high-dose cohort was soon closed when comparable activity of the doses was shown in relapsed or refractory patients with CLL/SLL.46 Eventually, 27 patients received 420 mg and 4 patients received 840 mg daily doses. Analysis was based on pooled data because results for the two dose cohorts were similar. The median follow-up was 22.1 months. Objective response was observed in 22 of 31 patients (71%), with 4 achieving complete response (13%), 17 with PR (55%), and 1 with nodular PR (3%). In addition, 4 patients (13%) achieved a PR with lymphocytosis (PRL) and 3 (10%) had stable disease. Response was independent of Rai stage, 17p13.1 or 11q22.3 deletion, and IGHV mutation status. The 24-month PFS and OS rates were 96.3% and 96.6%, respectively. Median PFS was not reached. Response was durable in the above studies, and the median duration of response (DOR) was not yet reached after a median follow-up of 27.2 months.47 Interim results of another single center phase 2 trial of single agent ibrutinib in CLL was reported at the ASH 2013 meeting.49 The first cohort included patients with 17p deletion, and the second cohort included patients 65 years or older without 17p deletion. At 6 months, 53% of 21 patients in the 17p deletion cohort achieved PR (an additional 43% of patients achieved PRL), and 81% of 26 patients in the elderly cohort had PR (an additional 9% of patients had PRL). The difference was probably because of slower clearance of treatment-induced lymphocytosis in patients with 17p deletion. The estimated event-free survival rate for the entire population at 14 months was 93%. These results were comparable to those previously published.46,48 The efficacy of ibrutinib in patients who had relapsed or refractory CLL/SLL with 17p deletion is under investigation in a phase 2 trial (RESONATE-17), the interim results of which were presented at the ASH 2014 meeting.50 One hundred thirty-seven patients with CLL and seven with SLL were included in this analysis, with a median age of 64 years and a median of two prior therapies. Investigator-assessed overall response rate (ORR) was 82.6%, including 17.4% PRL. At a median follow-up of 13.0 months (range 5 0.5–16.7 months), the median PFS and DOR had not been reached. At 12 months, 79.3% of patients were alive and progression-free. These results suggest that ibrutinib remains an effective therapy for patients with CLL/SLL with 17p deletion, a traditional high-risk factor. Ibrutinib compared with other single agents for CLL/SLL
A multicenter, open-label, phase 3 study (RESONATE) compared ibrutinib vs. ofatumumab in patients with relapsed or refractory CLL or SLL.51 Three hundred ninety-one patients were randomized into the oral ibrutinib group (420 mg daily; n 5 195) or the intravenous ofatumumab group (300 mg at week 1, 2000 mg weekly for 7 weeks, and then every 4 weeks for 16 weeks; n 5 196). The ORR was significantly higher in the 459
Table 1 Published clinical trials of ibrutinib Study
Phase
Disease type
No. of patients
Regimen
Outcome
Advani (2013)45
1
NHL (R/R)
56
Ibrutinib
ORR 60% (CR 16%, PR 44%) (50 patients evaluable for response) Response seen: CLL/SLL: 11/16 (2 CR) MCL: 7/9 (3 CR) DLBCL: 2/7 FL: 6/16 (3 CR) WM: 3/4 MZL: 1/4 Median PFS 13.6 mo
Wang (2013)58
2
MCL (R/R)
111
Ibrutinib
ORR 68% (CR 21%, PR 47%) Median PFS 13.9 mo 18-mo OS 58%
Byrd (2013)46
1b/2
CLL/SLL (R/R)
85
Ibrutinib
ORR 71% (CR 2%, PR 68%), PRL 18% 26-mo PFS 75% 26-mo OS 83%
O’Brien (2014)48
1b/2
CLL/SLL (untreated)
31
Ibrutinib
ORR 71% (CR 13%, PR 55%, nPR 3%), PRL 13% 24-mo PFS 96.3% 24-mo OS 96.6%
Byrd (2014)51
3
CLL/SLL (R/R)
391
Ibrutinib (n 5 195) vs. ofatumumab (n 5 196)
ORR 42.6%, PRL 20% 6-mo PFS 88% 12-mo OS 90%
Burger (2014)53
2
CLL/SLL (high risk)
40
Ibrutinib plus rituximab
ORR 95% (CR 8%, PR 87%) (46 patients evaluable for response) 18-mo PFS 78.0% 18-mo OS 83.8%
Younes (2014)65
1b
NHL (untreated)
33
Ibrutinib plus R-CHOP
ORR 94% (CR 72%, PR 22%) (32 patients received R-CHOP) Response seen: DLBCL: 22/23
Maddocks (2014)66
1/1b
NHL (untreated)
48
Ibrutinib plus rituximab and bendamustine
ORR 72% (CR 52%, PR 20%) (46 patients evaluable for response) Response seen: MCL: 16/17 (13 CR) DLBCL: 6/16 (5 CR) FL: 9/10 (5 CR) MZL: 1/1 Transformed: 1/2 (1 CR) 2-y PFS 50.3% 2-y OS 56.5%
CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NHL, non-Hodgkin’s lymphoma; nPR, nodular partial response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial €m’s macroglobulinemia. response; PRL, partial response with lymphocytosis; R/R, relapsed or refractory; SLL, small lymphocytic lymphoma; WM, Waldenstro
ibrutinib group (42.6%) than in the ofatumumab group (4.1%). An additional 20% of patients in the ibrutinib group achieved PRL. At a median follow-up of 9.4 months, ibrutinib significantly prolonged the duration of PFS compared to ofatumumab (not reached vs. 8.1 months; hazard ratio 5 0.22; 95% confidence interval 5 0.15–0.32; P < 0.001). The 6-month PFS rate was 88% in the ibrutinib group and 65% in the ofatumumab group. Ibrutinib also significantly increased the OS rate when compared with ofatumumab, with a 12-month OS rate of 90% vs. 81% (hazard ratio 5 0.43; 95% confidence interval 5 0.24–0.79; P 5 0.005). Of note, the survival benefits of ibrutinib were achieved regardless of 17p13.1 deletion status or resistance to purine analogues. An updated analysis of this study was presented 460
at the ASH 2014 meeting.52 Based on the results from this study, the FDA approved ibrutinib for use in patients with CLL with 17p deletion in July of 2014. A phase 3 study of ibrutinib vs. rituximab in relapsed or refractory CLL/SLL, and another randomized, multicenter, open-label, phase 3 trial studying ibrutinib vs. chlorambucil in elderly patients with untreated CLL/SLL (RESONATE-2) are ongoing. Ibrutinib in combination with chemoimmunotherapy for CLL/ SLL
Combination of ibrutinib with CD-20 antibodies has been investigated in multiple clinical trials. A single-arm phase 2 study evaluated the combination of ibrutinib and rituximab in patients VOLUME 97 NUMBER 5 | MAY 2015 | www.wileyonlinelibrary/cpt
Table 2 Partially reported ongoing clinical trials of ibrutinib Study
Phase
Disease type
No. of patients
Regimen
Outcome
Farooqui (2013)
2
CLL/SLL (elderly, or with 17p deletion)
53
Ibrutinib
PR 66%, PRL 28% 17p deletion cohort (n 5 21): PR 53%, PRL 43% Elderly (65) cohort (n 5 26): PR 81%, PRL 9% 14-mo EFS 93%
O’Brien (2014)50
2
CLL/SLL (R/R, with 17p deletion)
144
Ibrutinib
ORR 82.6% (including 17.4% PRL) 12-mo PFS 79.3%
Jaglowski (2014)54
1b/2
CLL/SLL (R/R)
71
Ibrutinib plus ofatumumab
ORR 71–100% 12-mo PFS 85–90%
Sharman (2014)55
2
CLL and MCL (R/R)
33 CLL 7 MCL
Ibrutinib plus ublituximab
CLL (n 5 18): ORR 94% (CR 5.5%) MCL (n 5 6): ORR 83% (CR 50%)
Brown (2013)56
1b
CLL/SLL (R/R)
30
Ibrutinib plus bendamustine and rituximab
ORR 93% (CR 17%, PR 67%, nPR 10%), PRL 3% 12-mo PFS 90%
Pollyea (2014)57
1
CLL/SLL (R/R)
11
Ibrutinib plus lenalidomide
PR 100% (9 patients evaluable for response)
Wang (2014)60
2
MCL (progressed after lenalidomide)
120
Ibrutinib
ORR 62.7% (CR 20.9%) Median PFS 10.5 mo 18-mo OS 61%
Wang (2014)61
2
MCL (R/R)
50
Ibrutinib plus rituximab
ORR 87% (CR 38%, PR 49%) (45 patients evaluable for response)
Wilson (2012)62
2
DLBCL (R/R)
70
Ibrutinib
ABC subtype (n 5 25): ORR 40% (CR 8%, PR 32%) 1 PR in GCB subtype (n 5 19) No response in unclassified (n 5 13)
Fowler (2012)63
1
FL (R/R)
16
Ibrutinib
ORR 54.5% (CR 27.3%, PR 27.3%) (11 patients evaluable for response) Median PFS 13.4 mo
Bartlett (2014)64
2
FL (R/R)
40
Ibrutinib
ORR 30% (CR 2.5%, PR 27.5%) Median PFS 9.9 mo
Christian (2014)67
1
NHL (R/R)
13
Ibrutinib plus lenalidomide
CR in 2 of 4 patients with DLBCL PR in 1 MCL and 1 transformed FL
Treon (2013)68
2
WM (R/R)
63
Ibrutinib
Best ORR (MR or better) 81% (4 VGPR, 32 PR, 15 MR) Major response rate (PR or better) 57.1%
Vij (2014)69
2
MM (R/R)
69
Ibrutinib 6 dexamethasone
Best response seen with higher dose ibrutinib plus dexamethasone (n 5 20): 1 PR, 4 MR
Jones (2014)70
2
HCL
8
Ibrutinib
Marrow clearance seen in first patient undergoing evaluation
49
ABC, activated B-cell-like; CLL, chronic lymphocytic leukemia; CR, complete response; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; FL, follicular lymphoma; GCB, germinal center B-cell-like; HCL, hairy cell leukemia; MCL, mantle cell lymphoma; MR, minor response; NHL, non-Hodgkin’s lymphoma; nPR, nodular partial response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PRL, partial response with lymphocytosis; R/R, relapsed or €m’s macroglobulinemia. refractory; SLL, small lymphocytic lymphoma; VGPR, very good partial response; WM, Waldenstro
with CLL with high-risk features.53 Forty patients were enrolled, among whom 20 had 17p deletion or TP53 mutation (16 previously treated, 4 untreated), 13 had disease relapse with 11q deletion, and 7 had PFS less than 36 months after first-line chemoimmunotherapy. Treatment consisted of oral ibrutinib (420 mg daily in 28-day cycles continuously) and intravenous rituximab (375 mg/m2 weekly during cycle 1, and once every 4 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 5 | MAY 2015
weeks until cycle 6). At a median follow-up of 16.8 months, 37 of the 39 patients (95%) evaluable for response assessment achieved complete (3; 8%) or partial (34; 87%) remission. Median DOR was 15.44 months. The 18-month PFS and OS rates were 78.0% and 83.8%, respectively, for all 40 patients. In the 20 patients with 17p deletion or TP53 mutation, the PFS and OS rates were 72.4% and 78.4%, respectively, which did not 461
differ significantly from those in patients without these genetic alterations (P 5 0.412 and 0.235 for PFS and OS, respectively). Of note, fewer patients in this study had persistent lymphocytosis than with ibrutinib single-agent treatment seen in other trials, suggesting that CD20 antibody may alleviate ibrutinib-induced lymphocytosis. Combination of ibrutinib with the second generation CD20 antibody ofatumumab for relapsed or refractory CLL/SLL and related diseases (prolymphocytic leukemia, Richter’s transformation) is being studied in a phase 1b/2 trial, and the interim results were reported at the ASCO 2014 meeting.54 Seventy-one patients were treated with ibrutinib (420 mg daily in 28-day cycles continuously) and ofatumumab (300/2000 mg, weekly 3 8 and then monthly 3 4) in three different administration sequences. Group 1 patients received ofatumumab starting with cycle 2; group 2 patients received concurrent treatment starting with cycle 1; and group 3 patients received ibrutinib starting with cycle 3. ORR in CLL/SLL was 100% in group 1, 79% in group 2, and 71% in group 3. At 12 months, PFS rates were 89%, 85%, and 90% in groups 1, 2, and 3, respectively. Combination of ibrutinib with the novel third generation CD20 antibody ublituximab for relapsed or refractory CLL and MCL is being studied in a phase 2 trial, and the interim results were reported at the ASH 2014 meeting.55 Thirty-three patients with CLL and seven patients with MCL have been enrolled to date, who received ibrutinib (420 mg for CLL, 560 mg for MCL, continuously) and ublituximab (600 or 900 mg for CLL, 900 mg for MCL, days 1, 8, and 15 in cycle 1 and day 1 in cycles 2–6) concurrently. At the time of report, 24 of 40 patients were evaluable for response. ORR was 94% for CLL (18 patients, 5.5% CR) and 83% for MCL (6 patients, 50% CR). Consistent with the effect seen with ibrutinib and rituximab combination,53 addition of ublituximab seemed to mitigate ibrutinib-related lymphocytosis seen with ibrutinib monotherapy. Collectively, the above data strongly suggest that ibrutinib in combination with CD20 antibodies is a very promising strategy to treat patients with relapsed or refractory CLL/SLL. How this combination compares with chemoimmunotherapy as frontline therapy is currently being studied. In a few ongoing clinical trials, the ibrutinib and rituximab combination will be compared with FCR or bendamustine plus rituximab (BR), and ibrutinib plus ofatumumab will be compared with chlorambucil plus ofatumumab. Combination of ibrutinib with chemoimmunotherapy is under investigation in CLL/SLL as well. A phase 1b trial studied the combination of ibrutinib with BR for the treatment of relapsed or refractory CLL/SLL, and the final results were reported at the ASH 2013 meeting.56 Thirty patients were enrolled, with a median age of 62 years and a median of two prior therapies. Treatment consisted of ibrutinib (420 mg daily), bendamustine (70 mg/m2 on days 1–2 of cycle 1 and day 1 of cycles 2–6), and rituximab (375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2–6). With a median treatment duration of 16 months, the ORR was 93% (5 CRs, 20 PRs, and 3 nodular PRs), and one additional patient (3%) achieved PRL. The responses were independent of high-risk features. The estimated 12-month 462
PFS rate was 90%. These encouraging results prompted a phase 3 study (HELIOS), which is currently ongoing. The combination of ibrutinib with FCR is being studied for untreated younger patients with CLL in a phase 2 trial (iFCR). These studies will further define the benefits of adding ibrutinib to chemoimmunotherapy in CLL/SLL. Combination of ibrutinib with lenalidomide for CLL is also under investigation. Interim results of an ongoing phase 1 trial were reported at the ASH 2014 meeting.57 Eleven patients with relapsed or refractory CLL/SLL were enrolled to date. Ibrutinib was given continuously at a fixed 420 mg daily dose. Lenalidomide was given starting from the second month (cycle 1) for 12 monthly cycles, with four dose escalation cohorts (2.5, 5, 7.5, and 10 mg) planned. At the time of report, nine patients were evaluable, with a median of eight treatment cycles completed. The ORR was 100% (all PRs). All nine patients remained alive with a median follow-up of 263 days. The response rate was exceptionally high, although further data are needed to evaluate this potentially powerful combination strategy. Further addition of rituximab to the ibrutinib and lenalidomide combination is being studied in relapsed or refractory CLL/SLL. MANTLE CELL LYMPHOMA Single agent ibrutinib in relapsed or refractory MCL
A phase 2 trial enrolled 111 patients with relapsed or refractory MCL, with a median age of 68 years and a median of three prior therapies.58 Ibrutinib was administered orally at a 560 mg daily dose. After an estimated median follow-up of 15.3 months, the ORR was 68%, with a CR rate of 21% and a PR rate of 47%. The response was independent of prior treatment with bortezomib (2 cycles vs.
