Ibrutinib for the treatment of Waldenström macroglobulinemia.

Drug Profile

Ibrutinib for the treatment of Waldenstro¨m macroglobulinemia Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/05/15 For personal use only.

Expert Rev. Hematol. Early online, 1–11 (2015)

Rajshekhar Chakraborty, Prashant Kapoor, Stephen M Ansell and Morie A Gertz* Mayo Clinic, Rochester, MN, USA *Author for correspondence: Tel.: +1 507 284 3725 Fax: +1 507 266 0972 [email protected]

Waldenstro¨m macroglobulinemia (WM) is a B-cell non-Hodgkin lymphoma (NHL) characterized by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Until recently, there was no drug specifically approved for WM by the US FDA, leading to wide variations in therapeutic strategies across the globe. Ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, is the first drug approved specifically for WM by the FDA after a clinical trial showed impressive response in previously treated WM. Ibrutinib is a non-stem cell toxic and non-neurotoxic option and suitable for long-term oral maintenance therapy, with the potential of improving survival in WM. With identification of novel genetic mutations impacting response to ibrutinib, it would be possible to individualize therapy based on MYD88 and CXCR4 genotypes. However, long-term safety and efficacy data are required, and cost-effectiveness needs to be addressed before ibrutinib can gain widespread acceptance for front-line therapy of WM. KEYWORDS: bruton tyrosine kinase . ibrutinib . immunoglobin M . lymphoplasmacytic lymphoma . Waldenstro¨m macroglobulinemia

Waldenstro¨m macroglobulinemia (WM) is a B-cell lymphoplasmacytic lymphoma characterized by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells, according to WHO and revised European–American Lymphoma classification criteria [1,2]. Clinical manifestations include hepatomegaly, splenomegaly and lymphadenopathy, and its diagnosis requires the presence of an IgM monoclonal protein in serum along with ‡10% lymphoplasmacytic cells in the bone marrow [2]. Clinical manifestations of IgM paraproteinemia include hyperviscosity syndrome, peripheral neuropathy, cryoglobulinemia and cold agglutinin hemolytic anemia [3]. An analysis of the 20-year data (1988– 2007) from the Surveillance, Epidemiology and End Results (SEER) program showed overall age-adjusted annual incidence of WM to be 3.8 per million, with an increased incidence seen in white males and the elderly population [4]. Around 1000–1500 new cases of WM are diagnosed in the USA every year [5]. Annual incidence in a European standard population was estimated to be 7.3 and 4.2 per million in men and women, respectively [6].

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10.1586/17474086.2015.1061427

Whole genome sequencing has identified novel activating somatic mutations in WM, including MYD88L265P and CXCR4WHIM [7]. Patients with MYD88L265P and CXCR4WHIM/ Nonsense(NS) mutations were found to have higher degree of bone marrow involvement, increased serum IgM levels and hyperviscosity syndrome requiring therapy [7]. Interestingly, the prevalence of MYD88L265P is as high as 90% in patients with WM, compared with 14–29%, 9, 7 and 3% in activated B-cell (ABC) type diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphoid tissue lymphoma (MALToma), splenic marginal zone lymphoma (SMZL) and chronic lymphocytic leukemia (CLL), respectively [8]. Activating mutation in MYD88 has been shown to trigger IL-1 receptor-associated kinase (IRAK) and Bruton tyrosine kinase (BTK)-mediated NF-kB signaling, which is critical for survival and proliferation of WM cells [8,9]. The common frontline regimens currently used for symptomatic WM include rituximabbased therapies, in combination with an alkylating agent (cyclophosphamide or bendamustine) or a purine nucleoside analog (or

2015 Informa UK Ltd

ISSN 1747-4086

1

Drug Profile

Chakraborty, Kapoor, Ansell, Gertz & Seidler

B-cell receptor P LYN/FYN

CD79A/CD79B

SYK

TLR-4

Expert Review of Hematology Downloaded from informahealthcare.com by Nyu Medical Center on 07/05/15 For personal use only.

P BTK

MYD88 dimer

pathways, including PI3K/Akt/mTOR, MYD88/IRAK and NF-kB pathways, among others [14]. Other than the BTK inhibitor Ibrutinib, novel agents that have shown activity in WM include proteasome inhibitors (PIs) bortezomib [15], carfilzomib [16] and oprozomib [17], mTOR inhibitor everolimus [18], immunomodulators thalidomide [19] and lenalidomide [20], Akt inhibitor perifosine [21], protein kinase C (PKC) inhibitor enzastaurin [22], PI3Kg inhibitor idelalisib [23], histone deacetylase inhibitors (HDAC) including panobinostat [24] and the alkylating agent bendamustine [25].

IL-1R

Bruton tyrosine kinase

BTK is a cytoplasmic enzyme, first identified in 1993 as a proto-oncogene found to be mutated in families with X-linked agammaglobulinemia, a primary immuFigure 1. B-cell receptor (BCR) signaling pathway. Antigen stimulation of BCR leads to aggregation of co-receptors CD79A and CD79B, which are phosphorylated and actinodeficiency disorder [26,27]. It is a memvated by LYN/FYN. Subsequently, SYK is recruited, which phosphorylates and activates ber of the Tec family of nonreceptor BTK. BTK subsequently leads to activation of NF-kB by a cascade of reactions, involving protein tyrosine kinases, which plays a phospholipase Cg2, protein kinase Cb and Ikb-kinase. Activation of Toll-like receptor pivotal role in B-cell function and recep(TLR)-4 and IL-1R lead to MYD88 dimerization and activation, which binds with phostor signaling [28]. B-cell receptor (BCR) phorylated BTK and activates downstream signaling pathways. BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; SYK: Spleen tyrosine kinase; TLR: Tollsignaling is important in survival of like receptor. benign and malignant B cells [29]. BCR is a transmembrane surface immunoglobulin receptor associated with the signaling both) [2]. Common adverse effects of cytotoxic therapies include proteins CD79A (Iga) and CD79B (Igb) [30]. Antigen binding cytopenias and potential for stem cell toxicity, including large to the BCR initiates a signal transduction cascade involving cell transformation and myelodysplastic syndrome in the long aggregation of BCR with CD79A and B. These receptors, in run. Variations in approaches exist, as suggested by a German turn, get phosphorylated by tyrosine kinases, LYN and SYK. study, which showed that patients treated in a private practice SYK induces PI3Kdelta and ultimately generates PIP3, a docksetting in a small German cohort to have a higher likelihood of ing site for the cytoplasmic BTK. Phosphorylated BTK in turn receiving a bendamustine-based regimen, compared with those activates phospholipase-Cg, which leads to calcium mobilizatreated in university hospitals [10]. There is an unmet need for tion and activation of downstream mitogen-activated protein the development of non-stem cell toxic and non-neurotoxic regi- kinase and NF-kB pathways [28,30]. BTK has also been shown mens suitable for continuous oral therapy in WM. A study to act as a signaling molecule in G-protein-coupled chemokine found the incidence of secondary malignancies (SMs) to be receptors CXCR4 and CXCR5, which mediate B-cell migration increased by almost 1.5-fold in WM patients compared with the and homing [31]. A simplified flow chart depicting BCR signalgeneral population, with a higher incidence of hematologic SMs ing pathway leading to activation of NF-kB and interaction of and certain solid-organ SMs such as lung, urinary tract and thy- BTK with MYD88 is shown in FIGURE 1. roid cancers [11]. The current National Comprehensive Cancer MYD88L265P, a recurrent somatic mutation in WM [8,9,32,33], Center guidelines for WM provide 10 options of non-stem cell has been shown to play a key role in the NF-kB signaling toxic regimens, including proteasome inhibitors and thalidomide pathway [9]. In 2011, a seminal study in ABC-subtype of in the front-line setting and 12 options for salvage therapy for DLBCL, a related malignancy that shares the oncogenically WM [12]. A study using the SEER database has shown improve- active MYD88 mutation with WM, demonstrated the role of ment of overall survival (OS) in WM patients over the past this mutation in promoting lymphoma cell survival by constidecade, including reduction in rates of both WM-related and tutive activation of NF-kB and the JAK kinase signaling pathnon-WM-related deaths in the 2001–2010 cohort, compared ways [34]. The study described the dependence of ABC DLBCL with cohort from 1991–2000 [13]. on adaptor protein, MYD88. Subsequently, studies in WM cell Novel therapies are being developed currently for WM based lines showed greater coimmunoprecipitation of MYD88 with on an improved understanding of deregulated molecular phosphorylated BTK in cells with MYD88L265P mutation [9]. NF-κB

doi: 10.1586/17474086.2015.1061427

Expert Rev. Hematol.


¨ m macroglobulinemia Ibrutinib for the treatment of Waldenstro

Mutated MYD88 Toll/IL-1 receptor (TIR) domain has been shown to display constitutive oligomerization, mimicking activated dimerized TIR domain, recruitment of endogenous MYD88WT for oligomer formation and subsequent activation of downstream NF-kB pathway [35]. Given the role of MYD88 in the Toll-like receptor (TLR) and IL-1 receptor (IL1R) signaling pathway by downstream recruitment of IRAK1 and IRAK4 [36], this study also showed that lipopolysaccharide or CpG oligonucleotides stimulation of TLR resulted in increased phosphorylation and activation of BTK and IkBa through MYD88. Interestingly, treatment with ibrutinib reduced MYD88–BTK complex formation and enhanced destruction of MYD88L265P bearing WM cells, highlighting the underlying mechanism central to the BTK inhibitor-induced apoptosis of WM cells. Ibrutinib Mechanism of action & preclinical studies

Ibrutinib (ImbruvicaTM, PCI- 32765) is formulated as 140-mg capsule for oral administration. This small, selective, irreversible inhibitor of BTK bonds covalently to cysteine-481 on the ATP-binding domain BTK [30,37]. On the basis of animal data, we found that ibrutinib is potentially hazardous to the fetus when administered during pregnancy [38]. A preclinical study of canine non-Hodgkin’ lymphoma (NHL) exhibited objective clinical responses in 3 of 8 dogs who were administered once daily PCI-32765 [39]. Increased tumor-cell killing of CD19 positive lymphoplasmacytic cells from four WM patients in vitro was seen upon dual inhibition of BTK and IRAK1/4 by ibrutinib and N-acyl 2-aminobenzimidazole, respectively, with no effect being observed in CD-19 positive cells from healthy donors expressing the MYD88WT genotype. Ibrutinib induces TLR-7- and TLR-9-mediated apoptosis in CLL cells in vitro and inhibits downstream TLR signaling pathways responsible for survival and a supportive microenvironment [40]. Ibrutinib inhibits IL-2 inducible kinase (ITK) as well and has been shown in murine models to enhance antitumor immune response, when administered along with a TLR-9 agonist by shifting the balance to Th-2 from a Th-1 immune response [41]. Pharmacodynamics & mechanisms of resistance

As indicated above, Ibrutinib reduces survival, proliferation and migration of malignant B cells by blocking BTK irreversibly. In patients with B-cell lymphoma, >90% occupancy of BTK active site was observed in peripheral blood mononuclear cells up to 24 h after ibrutinib doses of ‡2.5 mg/kg/day [38]. A Phase Ib-II multicenter study of ibrutinib in patients with relapsed or refractory CLL found occupancy of BTK to be 96– 99% as early as 4 h until 24 h after first-dose administration and found no apparent difference between doses of 420 and 840 mg [42]. Therapy-related lymphocytosis, occurring as a result of lymphocyte egress from lymph nodes, developed in almost 80% of patients by day 7, peaked at 4 weeks and declined slowly thereafter in this study. Persistent informahealthcare.com

Drug Profile

lymphocytosis after exposure to ibrutinib, irrespective of dose effect, likely represents a persistent, quiescent clone of lymphocytes that becomes dependent on the downstream regulators of BCR signaling pathway other than BTK and is not indicative of clonal evolution or poor outcome [43,44]. Peripheral lymphocytosis was also seen in WM after 6 months of ibrutinib initiation in patients who had attained major responses (‡ PR). As CXCR4 receptor is associated with homing of WM cells within the marrow, the demonstration of more pronounced peripheral lymphocytosis in those with MYD88L265PCXCR4WT compared with MYD88L265PCXCR4WHIM [45] was not an unexpected finding in this study. In a Phase II study on patients with multiple myeloma (MM), ibrutinib was shown to decrease cytokine and chemokine production, predominantly CCL3, CCL4 and chemokines responsible for adhesion and osteolysis in MM [46]. CXCR4WHIM nonsense mutations are found in nearly 30% of WM patients, being second in frequency after MYD88L265P [47]. CXCR4WHIM/NS mutation involves the C-terminal domain of CXCR4, which contains sites known to regulate CXCR4 signaling via the ligand stromal cell-derived factor-1 alpha (SDF-1a/CXCL12). These somatic mutations are located in the same region that is involved in the germline of patients with warts, hypogammaglobulinemia, recurrent infections, and myelokathexis (WHIM) syndrome, an immunodeficiency disorder characterized by noncyclic peripheral neutropenia attributed to the retention of neutrophils in marrow (myelokathexis). Engineered WM cells in vitro with CXCR4WHIM/NS and CXCR4WHIM/FS mutations showed impaired receptor internalization, increased Akt and ERK signaling and decreased apoptosis upon stimulation with SDF-1a [48,49]. Furthermore, these cells showed persistent Akt and ERK activation and reduced apoptosis after in vitro treatment with ibrutinib, which was reversed by the CXCR4 inhibitor, AMD3100 (Plerixafor). Ibrutinib-mediated apoptosis of CXCR4WHIM bearing cells was also restored by coadministration of CXCR4, Akt or ERK antagonists. Treatment with inhibitors of MYD88L265P triggered apoptosis of WM cells, which was not impacted by stimulation of CXCR4WHIM/NS or CXCR4WHIM/FS cells by SDF-1a, indicating a central role of MYD88L265P in the pathogenesis of WM. In patients with CLL, various mechanisms of resistance to ibrutinib have been identified, including C481S mutation of BTK, which leads to reversible inhibition, and gainof-function mutations of PLCg-2, leading to autonomous B-cell receptor activity [50]. In patients with mantle cell lymphoma (MCL), a somatic mutation in PLCg-2, PIM-1 and ErbB-4, all of which are involved in NF-kB signaling pathway, have been associated with progressive disease and resistance to ibrutinib [51]. As inhibition of NF-kB signaling is pivotal in ibrutinib-mediated destruction of WM cells, these mutations could also potentially mediate resistance to ibrutinib therapy in WM patients. Pharmacokinetics

A population pharmacokinetic (PK) model of ibrutinib was developed from three clinical studies, a Phase I dose-escalation study in recurrent B-cell malignancies [52], a Phase II study in doi: 10.1586/17474086.2015.1061427


Drug Profile


MCL [53] and a Phase Ib/II study in CLL [42] using a twocompartment PK model [54]. Patient demographics from pooled data on 245 patients in three studies showed 72.2% to be males and 89.4% white, with a mean age of 65.3 years. Since WM is seen predominantly in older white males as well [2], PK data from this study was extrapolated to WM patients. Ibrutinib was rapidly absorbed, with a high oral plasma clearance of approximately 1000 l/hour and a high apparent volume of distribution (Vd) at a steady state of around 10,000 l. Furthermore, the PK parameters were not affected by the dosage, indication for its use and the clinical trial studied. The average plasma concentration of ibrutinib after dosing 30 min before or 2 h following a high-fat meal was similar to that obtained after dosing immediately following a high-fat meal. Dosing after overnight fasting, however, reduced relative bioavailability to 67% compared with the meal conditions used in clinical trials and administration after a high-fat meal. Coadministration with antacids and increase in body weight marginally increased duration of absorption and Vd, respectively. Despite rapid absorption and elimination, with a half-life of 4–6 h, robust BTK occupancy was shown to be maintained in a study for at least 24 h, consistent with irreversible inhibition [52]. The mechanism of elimination of ibrutinib is predominantly metabolism by gut and hepatic cytochrome P450 3A4 enzyme, with almost 90% being eliminated in feces. The active metabolite is a dihydrodiol compound, PCI-45227, which has a 15-times lower BTK inhibitory activity compared with ibrutinib [37,38]. Since ibrutinib is metabolized predominantly by the liver, no dose adjustment is recommended for patients with renal impairment. According to US package insert, recommended dosage in patients with mild hepatic impairment (Child–Pugh class A) is 140 mg daily. However, recommendations for dose adjustment in those undergoing dialysis are not available yet, as such patients have been excluded in clinical trials [38]. It is not recommended to administer ibrutinib to patients with moderate or severe hepatic impairment (Child–Pugh classes B and C). Coadministration with ketoconazole, a strong CYP3A inhibitor was shown to increase maximum concentration (Cmax) by 29-fold, whereas rifampin, a strong CYP3A inducer decreased Cmax by more than 13-fold [37]. Similarly, overall exposure (area under the cover) to ibrutinib was increased 24-fold in the setting of CYP3A inhibition, and decreased 10-fold with CYP3A induction. Hence, caution should be exercised while prescribing ibrutinib with drugs altering CYP3A metabolism. Patients should be advised to avoid grapefruits and Seville oranges, which contain moderate inhibitors of CYP3A. Co-administration of ibrutinib with P-glycoprotein (P-gp) substrates such as digoxin that have a narrow therapeutic index may increase their blood concentration due to a high local concentration of ibrutinib in the gastrointestinal tract after an oral dose [38]. Clinical efficacy

In a study on patients with relapsed or refractory B-cell lymphoma and CLL, ibrutinib was shown to have ORR of 60%, with complete response (CR) of 16% [52]. Clinical efficacy doi: 10.1586/17474086.2015.1061427

data for ibrutinib in WM are available from a three-site Phase II trial conducted by Treon et al. [45] in patients with refractory and/or relapsed WM. Initial intended dosing in this trial was ibrutinib 420 mg orally once daily continuously for twenty-six 4-week cycles or until disease progression or serious adverse effects (SAEs) developed, but the protocol was subsequently amended to allow its use beyond 26 weeks in patients without disease progression. Sixty-three previously treated patients, of which, 25 (40%) were refractory to most recent regimen were enrolled in this trial. The median age at baseline was 63 years, and patients had received a median of two prior therapies. Sanger sequencing demonstrated that 89% of patients harbored MYD88L265P and 34% had CXCR4WHIM mutations. Median duration of ibrutinib therapy was 19.1 months (range, 0.5–29.7 months). Overall and major response (MR) rates were 90.5 and 73%, respectively, with the median time to at least a minor and partial response being 4 and 8 weeks, respectively. There was, however, no evidence of a complete response (CR) in any patient, and very good partial remission was the best achievable response in 10 (16%) patients. At best response, the median serum IgM levels declined from 3520 to 880 mg/dl, hemoglobin rose from 10.5 to 13.8 g/dl and bone marrow involvement declined from 60 to 25% (p < 0.001). Highest ORR and MR rate were evident in patients with MYD88L265PCXCR4WT genotype (100 and 91.2%, respectively), followed by MYD88L265PCXCR4WHIM (85.7 and 61.9%, respectively) and MYD88WTCXCR4WT (71.4 and 28.6%, respectively). Similarly, the tumor genotype impacted the best serum IgM and hemoglobin responses as well. Interestingly, hemoglobin and M-spike levels improved in the face of modest or no improvement of WM burden in the bone marrow. Such discrepant findings have also been encountered with other therapies, and selective inhibition of STAT5, a BTK substrate that regulates IgM secretion [55], by ibrutinib could account for this observation. Serial computerized tomographic imaging showed improvement in adenopathy in 25 out of 37 (68%) patients and spleen size decreased in four out of seven (57%) patients who had baseline splenomegaly. Four patients on plasmapheresis, in whom ibrutinib was initiated for symptomatic hyperviscosity, responded well and plasmapheresis was successfully discontinued in these patients by the end of cycle 2 of therapy. Importantly, ibrutinib dose modifications are not required during plasmapheresis. Unlike rituximab, which is known to cause IgM flare in WM, IgM flare was not observed during ibrutinib therapy in any of the 63 patients. Five out of nine patients with IgM-related peripheral sensory neuropathy had symptomatic improvement on ibrutinib and neuropathic symptoms remained stable on therapy in the other four patients. At 24 months, the PFS and OS were 69.1 and 95.2%, respectively. Predictors of low PFS rates included high pretherapy International Prognostic Scoring System (IPSS) score for WM, more than three prior lines of therapy and MYD88WTCXCR4WT genotype. Dose reduction due to toxicity did not affect response rates or PFS. Expert Rev. Hematol.



In a Phase Ib–II study of ibrutinib in relapsed or refractory CLL, ORR was noted to be 71% irrespective of dose (420 vs 840 mg), and rates of PFS and OS were 75 and 83%, respectively, at 26 months [42]. Another study comparing ibrutinib with ofatumumab, a monoclonal anti-CD20 antibody, in previously treated CLL/SLL found significantly greater ORR in the ibrutinib group compared to the ofatumumab group (42.6 vs 4.1%, p < 0.001) [56]. PFS and OS were also greater in the ibrutinib group in this study. While ofatumumab is currently being evaluated in WM, it has not been compared with ibrutinib in WM with randomized studies. A Phase II open-label multicenter study of ibrutinib in DLBCL showed a meaningful response in those with ABC-type DLBCL with an ORR of 40%, CR 8% and PR 32% [57]. Of note, ABC-type DLBCL harbors MYD88L265P mutation in 14–29% [34,58] and gain-of-function mutation of CD79B in 21% of cases [59], leading to constitutive BCR activation. Only one patient in germinal center B-cell like DLBCL attained PR. All patients with both CD79B and MYD88 mutations responded, but those with only MYD88 mutation (n = 4) did not respond to ibrutinib in this study, indicating an alternative pathway for BCR signaling in such patients. Genome-wide SNP array has identified CD79B/ CD79A mutations in 17q region in 15% of WM patients [60]; however, impact of such mutations on response to ibrutinib in WM is unclear. In relapsed and/or refractory MCL, ibrutinib has been shown to produce an ORR of 68% with CR of 21% and PR rates of 47%. Median PFS was estimated to be 13.9 months at a median follow-up of 15.3 months, with an OS rate of 58% at 18 months. An in vitro study has shown that ibrutinib has the potential to antagonize rituximab-dependent natural killer (NK) cell-mediated cytotoxicity on CD20 positive lymphoma cells by irreversibly binding to ITK of Fc-receptor (FcR) stimulated NK cells [61] and led the investigators to propose sequential ibrutinib-rituximab use over concurrent approach. However, a recent Phase II study of ibrutinib and rituximab in patients with high-risk CLL showed encouraging activity of the two agents used together with an 18-month PFS of 78% [62]. Since rituximab-based combination therapy is the current standard of care for WM [2], this study provides reassurance regarding potential of combination therapies with ibrutinib in the future and a Phase III study of ibrutinib with rituximab in WM is currently underway (NCT02165397). Safety & tolerability

In the Phase III study of ibrutinib in WM, toxicities were moderate and generally similar to those observed in the CLL and MCL studies. Common toxicity criteria grade ‡2 therapyrelated toxicities in WM included neutropenia (22%) and thrombocytopenia (14%), which were more commonly seen in heavily pretreated patients, atrial fibrillation (5%) in patients with a history of arrhythmia, procedure-related bleeding (3%) and recurrent epistaxis associated with fish-oil supplements (3%) [45]. Previously, in vitro and ex vivo platelet activation, mediated by collagen and von Willebrand Factor has been shown to be affected by ibrutinib, with a mild bleeding informahealthcare.com

Drug Profile

diathesis in some patients [63]. Two to three days of therapy cessation was enough for platelet aggregation recovery. A study has shown the potential inhibition of the cardiac PI3K/Akt pathway as a mechanism for increasing the risk of atrial fibrillation [64]. Atrial fibrillation resolved without any intervention in all WM patients in this study except for temporary cessation of ibrutinib therapy. Although ibrutinib was resumed in all three patients without any subsequent cardiac events, it should be used cautiously, particularly in elderly patients in whom such cardiac adverse effects are known to occur more frequently. Reasons for discontinuation of therapy included nonresponse (n = 1) in a patient with MYD88WT genotype, progressive disease (n = 7), thrombocytopenia (n = 1), development of myelodysplastic syndrome in a patient with a 5q deletion predating protocol therapy, hematoma after bone marrow biopsy (n = 1), infection, unrelated to ibrutinib (n = 1), disease transformation, possibly related to prior therapies (n = 2) and other miscellaneous factors (n = 6). Few infections were noted in patients receiving ibrutinib and levels of IgA/IgG remained stable, an advantage over some other neuropathy sparing approaches such as carfilzomib–rituximab–dexamethasone (CaRD) regimen where suppression of uninvolved immunoglobulins was common and associated with increased risk of infections. The US package insert of ImbruvicaTM contains warnings and precautions regarding risk of hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies and embryo-fetal toxicity [37,38]. No nonhematologic grade 4 toxicities were noted in Treon’s study. Grade 2 or higher infectious etiologies included herpes zoster (3%), pneumonia (8%), cutaneous infections, including subcutaneous abscess, cellulitis (8%) sinusitis (2%), endocarditis (2%) and urinary tract infections (2%). In a study on the outcome of CLL patients after discontinuation of ibrutinib in clinical trials, 26% of patients had stopped the medication, among which, 76% died shortly after, with a median OS of 3.1 months after discontinuation [65]. The majority of these patients had high-risk genetic signatures, including unmutated immunoglobulin heavy chain variable gene (94%), del(17p) (58%) and complex karyotype (54%). The rates of ibrutinib discontinuation increased with longer follow-up periods, 14% and 36% at a median follow-up of 9.5 and 21 months, respectively [65,66]. Overall, ibrutinib was relatively well tolerated in clinical trials and is a non-stem cell toxic and non-neurotoxic therapy. A comparison of the safety and efficacy of ibrutinib with other novel non-stem cell toxic and non-neurotoxic therapies currently in development for WM is shown in TABLE 1. Regulatory affairs & cost of treatment

Ibrutinib was first approved for MCL in previously treated patients in November 2013 and was one of the first agents to be approved through the US FDA Breakthrough Therapy Designation Pathway [37]. Subsequently, FDA granted accelerated approval to this agent for previously treated CLL patients in February 2014 based on preliminary data from a Phase Ib/II study in relapsed/refractory CLL [42,67]. Full approval by FDA was received for previously treated CLL as well as CLL with doi: 10.1586/17474086.2015.1061427

Drug Profile



Table 1. Comparison of ibrutinib with other novel non-stem cell toxic and non-neurotoxic drugs currently being developed for Waldenstrom’s Macroglobulinemia. Drug

Number of patients/ population

Overall response rate (ORR)

Follow up (months)

Overall survival (Mo.)

Progression free survival (Mo.)

Grade ‡3 adverse effects

Carfilzomib

31; Symptomatic WM naı¨ve to proteasome inhibitors

87%

15.4

NR

NR

Anemia, cardiomyopathy, hyperglycemia, Hyperlipasemia, neutropenia

[16]

Everolimus

60; relapsed and/ or refractory WM

73%

49

NR

21

Hematologic (cytopenias), infection, pulmonary (dyspnea and pleural effusion), gastrointestinal and metabolic (hyperlipidemia, hyperglycemia, hypoglycemia and hyponatremia)

[18]

Enzastaurin

42; Previously treated WM

38%

9.5

NA

NA

Leukopenia

[22]

Perifosine

37; Relapsed and/ or refractory WM

35%

19.5

NA

12.6

Hematologic (cytopenias), arthritis flares, blurred vision, ocular pain, infection, fatigue

[21]

Idelalisib

10; Relapsed WM (subset analysis)

10%

9.7

NA

NA

Neutropenia, transaminitis, diarrhea, pneumonia

[23]

Panobinostat


47%

7.7

NA

6.6

Hematologic (cytopenias), syncope, fatigue

[24]

Ibrutinib


90.5%

24

95.2% (OS rate)

69.1% (PFS rate)

Hematologic (cytopenias), atrial fibrillation, hematoma, epistaxis, herpes zoster

[45]

Ref.

NA: Not available; NR: Not reached.

17p deletion in July 2014. For WM, ibrutinib initially attained a breakthrough therapy designation, priority review and orphan product designation in February 2013, based on impressive preliminary clinical evidence of efficacy [68]. Subsequently, on 29 January 2015, the FDA expanded its indication to WM based on the data from the clinical trial by Treon et al. [68–70]. Although data are currently available for relapsed/refractory WM patients only, the FDA-approved label in WM is broad and does not restrict its use as salvage therapy alone. A randomized, double-blind, placebo-controlled, Phase III study of ibrutinib or placebo in combination with rituximab is ongoing for both treatment naı¨ve and previously treated WM patients (NCT02165397). The European Commission (EC) has granted approval of ibrutinib for treatment of relapsed and/ or refractory MCL and previously treated CLL, including those with 17p deletion or TP53 mutation [71–73]. The cost of a 1-month supply of ibrutinib 420 mg daily in the USA, based on an online database of prescription drug

doi: 10.1586/17474086.2015.1061427

prices, GoodRx, is $9361 or more, translating to an annual cost of around $112,000 [74]. In the Phase II trial mentioned above [45], the median duration of treatment was 19.1 months. Since ibrutinib is available as an FDA-approved alternative for treatment of CLL in the USA since February 2014, some data are available on the financial implications in CLL patients. A study was done to estimate the total pharmaceutical cost over a 10-year period after diagnosis using a hypothetical cohort of 100 newly diagnosed CLL patients under three scenarios: historical scenario prior to approval of ibrutinib and idelalisib, current scenarios A (after approval of ibrutinib as salvage therapy) and B (after approval of idelalisib as salvage therapy) and a potential future scenario anticipating use of ibrutinib as a first-line therapy [75]. Estimated 10-year pharmaceutical cost per treated patient in the historical scenario was $157,446, current scenario A was $268,788, current scenario B was $217,557 and the potential future scenario was $566,002. Total 10-year out-ofpocket cost for patients insured under Medicare part-D increased



from $325 per treated patient in historical scenario to $8800 per treated patient in current scenario A and $35,564 per treated patient in the potential future scenario. Since dosing and frequency of administration are similar in CLL and WM, the data can be reasonably extrapolated to WM.


Conclusion

Although limited data are available currently on the efficacy of ibrutinib in WM, robust clinical efficacy, oral route of administration and favorable toxicity profile has led to optimism regarding its long-term use. Ibrutinib has become the first drug to be approved specifically for WM by the FDA. Identification of genetic signatures, which impact response to ibrutinib, will help in providing individualized therapy to WM patients. Ibrutinib’s clinical efficacy appears more favorable to other novel single agents and is comparable with combination therapies, although a head-to-head comparison is lacking so far (TABLE 1). In addition to currently available Phase II data with surrogate endpoint like ORR, further randomized studies are required with endpoints including PFS, OS, quality of life and incremental cost–effectiveness ratio for making mature conclusions on the role of ibrutinib in treatment of WM. Expert commentary

Ibrutinib has been a landmark in the quest for a novel therapeutic regimen in WM. Ibrutinib monotherapy has led to an impressive ORR, surpassing many novel targeted therapies. Impressive clinical efficacy of ibrutinib in CLL, MCL and ABCtype DLBCL, the pathogenesis of which entails constitutive activation of the BCR pathway, is a great incentive to test it further in WM, which harbors the MYD88L265P mutation in 90% of cases. As an increased incidence of secondary hematologic malignancies and large cell transformation is being reported in WM patients [11], there is a need for non-stem cell toxic therapies. Ibrutinib has been adopted by the recent National Comprehensive Cancer Center guidelines for treatment of WM [12]. Neurotoxicity, a dose-limiting adverse effect of some novel agents, including PIs and immunomodulators, has not been seen with ibrutinib. Other than cytopenias, SAEs of ibrutinib, which remain a concern, include atrial fibrillation (approximately 5%) and bleeding complications including gastrointestinal (GI) hemorrhage. As WM is more common in the elderly population, early identification of bleeding and cardiac complications, to which this age group is more prone, is necessary. Long-term data are required to ascertain the duration of response and resistance to ibrutinib in WM patients. Cost remains a concern, especially given the potential for long-term maintenance therapy. Five-year view

There will be a considerable interest in targeting WM with BTK inhibitors in the future, given the identification of recurrent somatic mutations, which constitutively activate BTK and downstream signaling pathways. Clinical trials of ibrutinib, both as monotherapy and in combination with rituximab are in progress (TABLE 2). As mentioned earlier, Kohrt et al. had informahealthcare.com

Drug Profile

demonstrated that ibrutinib antagonizes rituximab-mediated NK cell-mediated cytotoxicity, especially antibody-dependent cellular cytotoxicity) [61]. However, in physiologically relevant conditions, simulated by exposing ibrutinib for 2 h and then washing it off, obinutuzumab-mediated antibody-dependent cellular cytotoxicity was shown to be minimally affected by ibrutinib pretreatment, supporting the use of combination therapies and allaying prior doubts [76]. Combination regimens with lenalidomide and bendamustine are also being evaluated in patients with WM. The combination of ibrutinib with ublituximab (TG-1101), a novel glycoengineered anti-CD20 monoclonal antibody, was shown to be highly active with an ORR of 94 and 83% in CLL and MCL, respectively, in a Phase II trial, with a favorable toxicity profile [77], laying the framework for further testing in WM. The clinical outcome of ibrutinib-resistant patients should be addressed in future trials. As poor OS and limited duration and response to subsequent therapy has been demonstrated in patients with CLL and MCL who failed ibrutinib [65,78], it would be important to monitor patients with WM closely upon discontinuation of ibrutinib. The combination of ibrutinib with other targeted therapies, which could block multiple checkpoints in the BCR signaling pathway, could be important to prevent resistance. An inhibitor of SYK, a kinase responsible for BTK phosphorylation and an antiapoptotic protein, B-cell lymphoma 2 (Bcl-2), has been shown to increase ibrutinib sensitivity of human ABC-type DLBCL cell lines and resensitize ibrutinib-resistant B-lymphoma cells with C481S BTK and R665W PLCG2 mutations by inhibiting cell growth, calcium mobilization, adhesion and migration [79]. Another study showed synergistic cytotoxicity of ibrutinib with the Bcl-2 antagonist ABT-199 (GDC-0199) in MCL and CLL cell lines [80]. In a preclinical study in WM cell lines, including ibrutinib- and bortezomib-resistant subclones, ABT-199 was shown to complement anti-WM activity of ibrutinib and bortezomib and restore sensitivity to these drugs as well [81]. A dual PI3Kd/g inhibitor, RP6530, was shown to overcome ibrutinib resistance of DLBCL cells in vitro and enhance its activity in ibrutinib sensitive cells [82]. The adverse effect of the CXCR4WHIM mutation on ibrutinib response in WM was abrogated in vitro by addition of the Bcl-2 antagonist ABT-199, which triggered apoptosis in WM cell lines, irrespective of CXCR4 mutational status. WM cells have been shown to express high levels of chemokine and adhesion receptors, including CXCR4 and VLA-4, responsible for transendothelial migration and homing [83]. Administration of the CXCR4 inhibitor AMD3100 along with ibrutinib could potentially mitigate ibrutinib resistance in WM cells harboring CXCR4WHIM mutations and should be tested in future clinical trials [49,84]. The long-term safety and efficacy of AMD3100 have been established in patients with WHIM syndrome in a Phase I trial, which should be reassuring for further testing in WM [85,86]. Nicotinamide phosphoribosyl transferase (NAMPT) is involved in nicotinamide adenine dinucleotide (NAD+)-directed NF-kB signaling and was shown to play a doi: 10.1586/17474086.2015.1061427

Drug Profile



Table 2. Currently ongoing clinical trials on ibrutinib in Waldenstro¨m macroglobulinemia. Study title

Patient population

Study design

Intervention

Primary endpoint

Secondary endpoint

Ibrutinib (PCI-32675) with rituximab in adults with WM; NCT02165397; Phase III

Untreated or previously treated WM

Randomized double-blind; primary purpose: arm a: ibrutinib plus rituximab; arm b: placebo plus rituximab; arm c: ibrutinib

Ibrutinib: 420 mg orally once daily; placebo capsules orally; rituximab: 375 mg/m2 once weekly for 4 weeks, with second set of 4 weekly infusion after 3-month interval

PFS

ORR, rise in hemoglobin, TTnT, OS and adverse effects

Ibrutinib (PCI-32675) in WM; NCT01614821; Phase II

Previously treated WM

Open-label; primary purpose: treatment

Ibrutinib: 420 mg orally once daily

ORR

PFS, safety and tolerability

Lenalidomide and ibrutinib in patients with B-cell NHL; NCT01955499; Phase I

Relapsed or refractory B-cell NHL (including WM)


Oral lenalidomide on days 1–21 and oral ibrutinib on days 1–28, with repeat courses every 28 days

Toxicity and MTD

Response rates and survival

Rituximab/ bendamustine/ PCI-32765 in DLBCL, MCL or indolent NHL; NCT01479842; Phase I

Relapsed or refractory DLBCL, MCL or indolent NHL (Including WM)


PCI-32675 oral daily on days 1–28, rituximab i.v. on day 1 and bendamustine hydrochloride i.v. on days 1–2, with repeat course every 28 days up to 6 courses

MTD

Frequency of adverse effects, response rates

DLBCL: Diffuse large B-Cell lymphoma; i.v.: Intravenous; OM: Outcome measure; OS: Overall survival; ORR: Overall response rate; PFS: Progression free survival; MCL: Mantle cell lymphoma; MTD: Maximum tolerated dose; NHL: Non-Hodgkin’s lymphoma; TTnT: Time to next treatment.

crucial role in the biology of MYD88 L265P expressing WM cells. The NAMPT inhibitor FK866 induced synergistic cytotoxicity in vitro by robust inhibition of NF-kB signaling, activation of caspases and intracellular NAD depletion [87]. Clinical trials of ibrutinib in combination with these experimental agents, showing activity in vitro, need to be conducted in WM to ascertain the feasibility of such combination regimens. Furthermore, with the development of newer BTK inhibitors, including AVL-292 and ONO-4059 [88], studies

should be conducted to compare the efficacy and safety of different BTK inhibitors in WM. Financial & competing interests disclosure

M Gertz has received support from Millenium Celgene Binding Site Onyx Med Learning Group Research to Practice. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues .

A highly prevalent somatic mutation MYD88 L265P that activates Bruton’s tyrosine kinase (BTK) and drives B-cell receptor signaling pathways has been identified in Waldenstro¨m macroglobulinemia (WM).

.

Ibrutinib, a potent, irreversible BTK inhibitor leads to decreased BTK-MYD88 complexing and has shown an impressive overall response rate of 90.5% in previously treated WM.

.

Success of ibrutinib, a non-stem cell toxic and non-neurotoxic option for WM has the potential to improve survival by allowing longterm oral maintenance therapy.

.

Although safety and efficacy data of ibrutinib monotherapy in WM are limited, promising results in WM as well as other B-cell receptor signaling pathway-dependent lymphomas, namely chronic lymphocytic leukemia, mantle cell lymphoma, activated B-cell type diffuse large B-cell lymphoma and follicular lymphoma serve as catalysts for assessment of effective combination of this recently approved monotherapy in WM.

doi: 10.1586/17474086.2015.1061427



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The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia.

Treatment of Waldenström's macroglobulinemia with alpha interferon.

Waldenström macroglobulinemia: from biology to treatment.

Immunochemotherapy in Waldenström macroglobulinemia - still the backbone of treatment.

The efficacy of ibrutinib in the treatment of Richter syndrome.

New approved indication for ibrutinib.

Ibrutinib.

Ibrutinib: Implications for Use in the Treatment of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia.

Ibrutinib: targeting the hidden CLL.

Ibrutinib-Associated Skin Toxicity: A Case of Maculopapular Rash in a 79-Year Old Caucasian Male Patient with Relapsed Waldenstrom's Macroglobulinemia and Review of the Literature.

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells.

Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenström's macroglobulinemia.

Ibrutinib: a new frontier in the treatment of chronic lymphocytic leukemia by Bruton's tyrosine kinase inhibition.

Rituximab and fludarabine or cyclophosphamide combination treatment for older waldenström macroglobulinemia patients.

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease.

Targets for Ibrutinib Beyond B Cell Malignancies.

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus.

Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

Autoimmune thrombocytopenia: a complication of fludarabine therapy in the treatment of Waldenstrom's macroglobulinemia.

Waldenström macroglobulinemia and autoimmunity: what's the connection?