Review

Emerging drugs for diffuse large B-cell lymphoma Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/06/15 For personal use only.

Expert Rev. Anticancer Ther. Early online, 1–13 (2015)

Patrizia Mondello1,2 and Anas Younes*2 1 Department of Human Pathology, University of Messina, Via C. Valeria, 98100 Messina, Italy 2 Lymphoma Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 330, New York, NY 10065, USA *Author for correspondence: [email protected]

Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma in western countries. Despite the addition of rituximab to chemotherapy, the prognosis is still poor and almost one-third of patients fail or relapse after first-line treatment. Gene expression profiling has identified three main signatures related to subgroups with different biological characteristics and responses to treatment. Novel agents targeting the oncogenic drivers of these subsets are currently under investigation with the aim of providing a tailored approach and avoiding unnecessary toxicity. Herein, we review the emerging therapies for DLBCL with a focus on preclinical and early clinical trials as well as future directions. KEYWORDS: Bcl-2 . bromodomain . DLBCL . HDAC . ibrutinib . lenalidomide . monoclonal antibodies . MYC . PI3K

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma subtype in western countries, accounting for approximately 30% of new cases of nonHodgkin’s lymphoma (NHL) [1]. Despite the improvement obtained by adding rituximab, a chimeric monoclonal anti-CD20 antibody, to conventional chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-CHOP), the prognosis is still poor with a 3-year overall survival (OS) less than 60% in the high-risk patients [2]. Gene expression profiling and DNA sequencing have provided new insights into DLBCL biology. Indeed, gene expression profiling has identified three DLBCL subtypes based on the cell of origin, namely germinal center B-cell like (GCB), activated B-cell like (ABC) and primary mediastinal B-cell [3]. Pathway activation varied among the three subtypes suggesting different pathogenetic bases and consequently different responses to standard treatment. Therefore, several drugs targeting the aberrant signaling pathways involved in these subsets are currently under investigation to allow for a more specific lymphoma treatment. Herein, we review the emerging therapies for DLBCL with a focus on preclinical and early clinical trials as well as future directions. Immunotherapy Unconjugated antibodies

Although rituximab has significantly improved the outcome of patients affected by DLBCL, a informahealthcare.com

10.1586/14737140.2015.1009042

part of them respond only partially or are even refractory. However, until now no studies have used rituximab at the maximum tolerated dose and so its real efficacy might be underestimated. Indeed, in recent years, several factors such as sex and body weight have been demonstrated to influence the clearance of this antibody [4], suggesting a possible explanation of the different efficacies of R-CHOP in certain subgroups of patients [4], who therefore might profit from higher doses of the drug. Nevertheless, to improve the biological and clinical activity of immunotherapy, new monoclonal antibodies (mAb) have been designed (TABLE 1) [5]. These agents have shown to be more efficient than rituximab, but they were used at much higher doses. Therefore, it is not yet clear whether their antitumoral effect is really superior or not, especially in light of the recent data regarding the pharmacokinetics of rituximab. Obinutuzumab (GA-101) is a Type II, glycoengineered, humanized anti-CD20 mAb that binds a different CD20 epitope from rituximab [6]. In vitro and in vivo studies suggested a potential improved efficacy compared with rituximab [7]. Encouraging results were recently observed in the Phase II GAUGUIN trial evaluating obinutuzumab in 40 heavily pretreated DLBCL and mantle cell lymphoma (MCL) patients who were treated with either a flat dose of 400 mg (DLBCL, n = 10; MCL, n = 11) or 800 mg (DLBCL, n = 15; MCL, n = 4). The overall response rate (ORR) was

 2015 Informa UK Ltd

ISSN 1473-7140

1

doi: 10.1586/14737140.2015.1009042 Fully human IgG4 anti-PD-1

Nivolumab

Lenalidomide

Immunomodulatory drug

Immunomodulatory drug

CAR-modified T cell anti-CD19

Disease R/R DLBCL

R/R DLBCL R/R DLBCL R/R NHL R/R DLBCL R/R DLBCL R/R R/R NHL R/R NHL R/R DLBCL R/R DLBCL

R/R NHL R/R NHL

R/R NHL

R/R DLBCL

Chemonaı¨ve DLBCL

Trial design Monotherapy [7]

Monotherapy [11] ICE/DHAP [12] Monotherapy [16] Monotherapy [17] Monotherapy [20] Monotherapy [21] Rituximab [23] Monotherapy [25] Monotherapy [26] Rituximab [27]

F+C [29] Monotherapy [33]

Rituximab [34]

Monotherapy [36]

R-CHOP [37]

64 (64)

40 (40)

45 (32)

217 (108)

15 (9)

39 (4) 55 (55) 52 (52)

122 (42)

82 (11)

66 (66)

62 (12) 11 (11)

61 (61)

81 (81)

40 (25)

Patients (n) (no DLBCL)

ORR 28% (for DLBCL), CR 7% PR 20% ORR 28%: CR 22, PR 6% ORR 27.5%: . ABC 53% . GCB 9% ORR 98% CR 80%

ORR 92% CR61.5%

ORR 74% ORR 43.9%, CR 25.4% ORR 31.1%

ORR 57% CR 24%

ORR 36%

ORR 72.7%

ORR 82% ORR 57%

ORR 11%, CR 4% ORR 59%, CR 31%

HD ORR 55% LD ORR 17%

Response rate

PFS 6.4 months: . ABC 6.2 months . GCB 1.7 months 2-year EFS 59%: . ABC 60% . GCB 59 2-year OS 78%: . ABC 83%, . GCB 75%

PFS 2.8 months. OS 10.2 months

DOR 4.5 months, PFS 2.3 months

DOR 9–22 months

DOR 3.4–8.2 months NA NA

PFS 5.4 months

–

16-month PFS 72%

DOR 6 months NA

DOR 6.9 months, PFS 2.5 months PFS 9.5 months

HD PFS 11.9 months LD PFS 6 months

Response duration

ABC: Activated B-cell like; ADC: Antibody–drug conjugate; CAR: Chimeric antigen receptor; CR: Complete response; DLBCL: Diffuse large B-cell lymphoma; DOR: Median duration of response; EFS: Event-free survival; F+C: Fludarabine and cyclophosphamide; GCB: Germinal center B-cell like; HDL: High dose (1600 mg); LD: Low dose (400 mg); mAb: Monoclonal antibody; NA: Not available; NHL: Non-Hodgkin lymphoma; ORR: Overall response rate; OS: Overall survival; PD-1: Programmed cell death protein 1; PFS: Progression-free survival; R/R: Relapsed/refractory; R-CHOP: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

KTE-C19

mAb anti-CD19 linked to maytansinoid DM4

Fully human IgG1 anti-PD-1

Pidilizumab

Coltuximab ravtansine

Bispecific T-cell engager antibody anti-CD19

Blinatumomab

mAb anti-CD22 linked to auristatin

Fully human Type I anti-CD20

Ofatumumab

Pinatuzumab vedotin

Glycoengineered, humanized Type II anti-CD20

Agent mechanism/ target

Obinutuzumab

CAR-T cell

ADC

Monoclonal antibodies

Agents

Table 1. Immunotherapy in DLBCL patients.

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Review Mondello & Younes

Expert Rev. Anticancer Ther.

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/06/15 For personal use only.

Emerging drugs for DLBCL

55% in the high-dose arm and 17% in the lower dose arm [8]. Given the treatment response of 27% of rituximab-refractory patients, the results appear promising and provide a rationale for a randomized trial that compares obinutuzumab versus rituximab in combination with CHOP in previously untreated DLBCL patients [9]. Ofatumumab (Arzerra) is a fully humanized Type I antiCD20 IgG1 kappa mAb [10], approved by the US FDA for the treatment of chronic lymphocytic leukemia (CLL). Unlike rituximab, ofatumumab binds both the small and large extracellular loops of the CD20 molecule, leading to a more efficient killing activity. The mechanisms of action are complement-dependent cytotoxicity and antibody-dependent cytotoxicity [11]. The efficacy and safety of ofatumumab as monotherapy were evaluated by Coiffeir et al. in 81 heavily pretreated, high-risk refractory/relapsed (R/R) DLBCL patients. The ORR was 11% with median duration of response of 9.5 months. Although the median progression-free survival (PFS) was 2.6 months, nine patients were progression-free for more than 18 months. [12]. The modest clinical activity demonstrated in this study was probably because the poor prognostic profile of the included cases. Matasar et al. investigated the feasibility of combining ofatumumab with chemotherapy [13]. Sixty-one R/R DLBCL patients were treated with ofatumumab in association with either ifosfamide, carboplatin and etoposide, or with cisplatin, cytarabine and dexamethasone, depending on the physician’s choice. The ORR and complete response (CR) rates achieved by these regimens were 59 and 31%, respectively [13]. These results appear comparable with those reported in the CORAL trial (ORR: 63%; PFS 9.5 months and overall survival (OS) 16.7 months) [14]. Based on these findings, a Phase III trial (ORCHARRD) randomized 447 patients with R/R DLBCL or grade 3b follicular lymphoma (FL) to receive ofatumumab or rituximab in combination with dexamethasone, cytarabine, cisplatin [15]. The ORR was 83% with a CR rate of 67% in patients relapsing following a remission greater than 1 year on prior rituximab therapy, and 55% with a CR rate of 30% in patients with early relapse or primary refractory disease. However, the trial did not meet its primary endpoint as there was no statistically significant difference in PFS between the treatment arms. In addition, ofatumumab treatment was associated with more frequent dose interruptions and delays because of infusion reactions and increased serum creatinine. Blinatumomab (MT103) is a bispecific T-cell engager antibody, which targets both CD19 (a marker ubiquitously expressed by B cells at all differentiation stages) and CD3 (a T-cell marker). Linking these two cell types and activating the T cells, this drug exerts cytotoxic activity on the B-cells [16]. Blinatumomab has recently received FDA approval for the treatment of acute lymphoblastic leukemia. In a Phase I study, 62 NHL patients (DLBCL, n = 12) underwent treatment with the recommended dose of blinatumomab achieving an ORR of 82%. Notably, over 60% of them maintained a durable response up to 3 years after therapy [17]. Preliminary data from informahealthcare.com

Review

an ongoing Phase II trial in R/R DLBCL [18] confirmed the efficacy of blinatumomab in this poor prognostic setting with an ORR of 57%. However, a high rate of grade ‡3 adverse events (AEs) was reported. Most of them were reversible and consisted of central nervous system toxicities (such as tremor, speech disorder, and disorientation) [19]. Overall, the treatment was tolerable and demonstrated a good antitumor activity in a setting with few therapeutic options. Pidilizumab is a humanized IgG1 mAb against programmed cell death protein 1 (PD-1), an immune checkpoint receptor that inhibits T cell activation upon interaction with its ligands PD-L1 and PD-L2. Increased PD-L1 expression has been reported in various lymphoid malignancies, and may allow these tumors to circumvent host antitumor immunity. Antibodies directed against PD-1 block the suppression of T-cellmediated immunity, ensuring normal immune responses. Pidilizumab has demonstrated to be safe and effective in DLBCL patients after autologous hematopoietic stem cell transplantation. In a Phase II study, 66 R/R DLBCL patients received pidilizumab for three cycles after the autologous hematopoietic stem cell transplantation. Overall, the 16-month PFS was 72%. Among 24 patients who remained PET-positive at the conclusion of salvage therapy, the 16-month PFS was 70%. Among 35 patients with measurable disease after autologous hematopoietic stem cell transplantation, the ORR after pidilizumab therapy was 51%. Pidilizumab was well tolerated and did not induce autoimmune toxicity or treatment-related mortality. PD-1 blockade appeared to be an efficient therapeutic option in a high-risk subset of patients with residual disease. Furthermore, it seems able to overcome the negative prognostic value of pretransplant-positive PET scan [20]. Further studies using this approach are warranted. Nivolumab (BMS-936558) is a fully human IgG4 monoclonal PD-1 receptor blocking antibody that has recently shown its high activity in lymphoid malignancies. A Phase I study enrolled 82 heavily pretreated lymphoma patients (B-NHL, n = 29; DLBCL, n = 11), who received nivolumab at a dose of 3 mg/kg every 2 weeks. The ORR in B-NHL was 28%: 36% in DLBCL patients (CR: 9%, partial response [PR] 27% and stable disease [SD] 27%). This treatment was demonstrated to be safe and tolerable [21]. Based on these promising results, a Phase II study in R/R DLBCL [22] is ongoing. Antibody–drug conjugate

Pinatuzumab vedotin, an antibody–drug conjugate (ADC) composed of a mAb against CD22 and the cytotoxic auristatin, has recently been designed. Once pinatuzumab vedotin binds its target receptor, it is internalized and the cytotoxic agent is released, leading to microtubule disruptions and subsequently to cell death. In this way, pinatuzumab vedotin can deliver a potent dose of the cytotoxin specifically to CD22+ cells [23]. A randomized, Phase II trial (ROMULUS trial) is evaluating R/R NHL patients either to pinatuzumab vedotin single agent or polatuzumab vedotin, a new CD79b ADC, plus rituximab. doi: 10.1586/14737140.2015.1009042

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Mondello & Younes

The preliminary results showed a fairly impressive ORR across the different histologies. More than half of the patients with DLBCL (57 and 56% with pinatuzumab and polatuzumab vedotin, respectively) and nearly two-thirds of the patients with FL (62 and 70% with pinatuzumab and polatuzumab vedotin, respectively) obtained a response to treatment. A considerable part of patients achieved CR, even those with DLBCL (24 and 15% with pinatuzumab and polatuzumab vedotin, respectively). The mPFS was similar in the two treatment-arms (5.4 and 5.2 months in CD22 ADC and CD79b ADC, respectively). The toxicity profiles were also fairly similar across the two different regimens. The most frequent AEs were grade 3/4 neutropenia and peripheral neuropathy [24]. Coltuximab ravtansine (SAR3419) is a humanized antiCD19 antibody conjugated to maytansinoid DM4, a highly potent tubulin inhibitor. This drug demonstrated significant activity on DLBCL in vitro and in vivo models [25]. Promising results were derived from a Phase I study enrolling 39 R/R NHL (DLBCL, n = 4) patients who received SAR3419 every 3 weeks for up to six cycles. Of 35 evaluable patients, 26 patients (74%) showed tumor shrinkage, with six objective responses. Time to progression in responding patients ranged from 27.9 to 44 weeks. Treatment was well tolerated and the dose-limiting toxicity was reversible eye toxicity (mostly blurry vision) observed at doses higher than 200 mg/m2 [26]. The STARLYTE Phase II trial confirmed the efficacy of SAR3419. Patients with previously treated DLBCL, including refractory disease to rituximab, underwent single agent SAR3419 at 55 mg/m2 weekly for 4 weeks and then biweekly until disease progression or discontinuation. Of the patients enrolled in the trial, 55 patients were evaluable for efficacy and 61 patients were evaluable for safety. The ORR was 43.9% in all the population (7 CR and 14 PR): 53.8% (CR 35.7% and PR 64.3%) in patients with relapsed disease, 26.7% (CR 6.6% and PR 20%) in those with refractory disease to the last treatment and 21.4% (CR 7.1% and PR 14.3%) in those with primary refractory disease. SAR3419 demonstrated a favorable safety profile with few treatment-related grade 3/4 AEs, which were mainly related to myelosuppression (neutropenia, thrombocytopenia and anemia were observed in 26.4, 9.9 and 6.6%, respectively) [27]. Recently, a Phase II study enrolling 52 R/R DLBCL patients evaluated the combination of SAR3419 with rituximab. The ORR was 31.1% in all the population: 58.3% in patients with relapsed DLBCL (n = 12), 42.9% in those with refractory disease to last regimen (n = 7) and 15.4% in those with primary refractory disease (n = 26). Overall, the activity of SAR3419 associated with rituximab seems moderate; however, the study population was of poor prognosis (60% refractory to first-line therapy). Indeed, the ORR in the relapsed DLBCL group was higher with respect to the refractory one. The combination therapy appeared to be safe without grade 3/4 peripheral neuropathy or ocular events [28]. Despite the encouraging results, the future development of this drug is hampered by the eye toxicity, even though it is reversible. With a highly competitive field of promising investigational agents, it doi: 10.1586/14737140.2015.1009042

is unlikely that SAR3419 will be incorporated in mainstream therapy of DLBCL. Chimeric antigen receptor-T cells

The past two decades have seen the development of an innovative type of immunotherapy using genetically modified T cells to express a chimeric antigen receptor (CAR) which recognizes and kills cells expressing specific targets on cancer cells [29]. At the present time, the most promising approach is targeting CD19, but other targets are currently being explored. Results from the Phase I/IIa study generated excitement because of the great efficacy of this T-cell immunotherapy in B-cell lymphoma. Fifteen R/R NHL patients (nine DLBCL and six indolent B-cell malignancies) received a single infusion of KTE-C19, a CD19-targeted CAR-modified T-cell therapy, after a conditioning regimen of cyclophosphamide and fludarabine. The ORR was 92% with CR of 61.5% and PR of 30.8%. Among seven evaluable patients with DLBCL, four patients experienced a CR, two patients had a PR and one patient had SD, for a 100% clinical benefit rate. The lengthy CRs obtained by numerous of these poor-risk patients are noteworthy. AEs associated with KTE-C19 were most frequent in the first 2 weeks after the beginning of treatment. A number of neurologic symptoms were reported, including confusion and obtundation, probably correlated to factors secreted by CART-cells. Overall, 27% of patients experienced grade 3/4 hypotension. One patient died suddenly as a result of an unknown cause 16 days after cell infusion [30]. A Phase I/II clinical trial to evaluate KTE-C19 in R/R DLBCL patients is ongoing to verify the reliable activity of this new approach. [31]. Future directions will refine the CAR platform to improve its efficacy and safety, and to test this novel therapy in combination with other treatments such as novel small molecules and other immunotherapies (e.g., anti PD-1 antibodies). Immunomodulatory drugs

Lenalidomide is an oral immunomodulatory drug with multiple mechanisms of action, including direct antitumor and immunomodulatory effects able to impact the immune system function and inhibit inflammation [32]. Witzing et al. evaluated lenalidomide as single agent in 217 R/R NHL patients (DLBCL = 49.8%; MCL = 26.3%, transformed large B-cell lymphoma [TL] = 15.2%; FL = 8.8%). The ORR was 28% (CR 7%, PR 20%) in the DLBCL subgroup with a median response time of 4.5 months. The mPFS was 2.3 months. Overall, the treatment was well tolerated and the more frequent grade 3/4 AEs were neutropenia (41%) and thrombocytopenia (18%) [33]. Lenalidomide was also evaluated in combination with rituximab in 45 patients with R/R NHL (DLBCL, n = 32; TL, n = 9; grade 3 FL, n = 4). Although the ORR was similar to the single agent results (28%), a higher CR rate was observed (22%). Nevertheless, PFS was 2.8 months and OS 10.2 months [34]. Yang et al. identified the higher efficacy of lenalidomide in ABC DLBCL because of the aberrant activation of NF-kB pathway in this lymphoma subtype. They Expert Rev. Anticancer Ther.

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Emerging drugs for DLBCL

demonstrated that lenalidomide downregulates the interferon regulatory factor 4 and inhibits NF-kB, JAK, and MYD88 signaling, leading to enhanced toxicity [35]. In a retrospective study, Hernandez-Ilizaliturri et al. reported a greater activity of lenalidomide in ABC DLBCL compared with the GCB subtype (ORR rate 53 vs 9%, respectively; p = 0.006). The mPFS was longer in non-GCB patients as well (6.2 vs 1.7 months, respectively; p = 0.004). Nevertheless, there was no difference in OS [36]. Based on these promising results, lenalidomide was evaluated in combination with R-CHOP (combination treatment known as R2CHOP) in 64 newly diagnosed DLBCL. ORR was 98% (59 of 60) with CR 80% (48 of 60). At 2-year follow-up, event-free survival and OS rates were 59 and 78%, respectively. Unlike R-CHOP treatment, no difference in 24-month PFS and OS was observed between GCB and non-GCB subtypes (60 vs 59%; p = 0.83 and 83 vs 75%; p = 0.61), meaning that lenalidomide overcomes poor prognostic factors of non-GCB subtypes [37] (TABLE 2). Because of the promising results, lenalidomide is being evaluated in several trials in newly diagnosed [38,39] as well as R/R DLBCL. [40–42]. Small molecules targeting oncogenic signaling pathways PI3K/AKT/mTOR pathway

Aberrant activation of PI3K/AKT/ mTOR signaling pathway is frequently observed in lymphoma [43]. A variety of molecules targeting various components of PI3K/AKT/mTOR pathway have been shown to inhibit lymphoma cell growth and proliferation in vitro and in animal models. In clinical trials, several small molecule inhibitors targeting PI3K pathway demonstrated clinical activity in patients with different types of lymphoma, but activity in DLBCL remains suboptimal (FIGURE 1 & TABLE 2) [44]. Idelalisib (CAL-101) is an oral inhibitor of the PI3K isoform p110d currently approved by the FDA for the treatment of R/R CLL, FL and small lymphocytic lymphoma. Despite the promising preclinical data [45], a Phase I study including only a handful of patients did not demonstrate activity of idelalisib in DLBCL [45]. On the contrary, it showed an ORR of 62% in MCL and 59% in indolent NHL [46]. Duvelisib (IPI-145) is an oral inhibitor of the PI3K isoforms p110d and g. In vitro data showed duvelisib to be more potent than idelalisib with 100-fold selectivity for p110d over p110g [47]. Preliminary data from Phase I study conducted in R/R NHL showed its safety and efficacy in B (n = 21, 2 CR, 9 PR, 5 SD) and T-cell (n = 6, 1 CR, 1 PR, 1 SD) malignancies. However, no data are available on the activity of duvelisib in DLBCL [48]. Copanlisib (BAY 80-6946) is a potent inhibitor of class I PI3K, isoforms p110a and d, which showed a broad antitumor activity in preclinical models [49]. A Phase I dose escalation study assessed the maximum tolerated dose of copanlisib at 0.8 mg/kg with promising clinical activity in the lymphoma setting [50]. Based on these data, a Phase II trial is currently evaluating the single agent effectiveness in 61 heavily pretreated NHL patients (FL, n = 13; CLL, n = 11; MZL, informahealthcare.com

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n = 3; DLBCL, n = 18; MCL, n = 7; TL, n = 5; PTCL, n = 4). At the interim analysis, encouraging results were observed in indolent lymphomas (ORR was 40 and 67% in FL and CLL, respectively) and in MCL (ORR 85%). In DLBCL, a modest 13% ORR was reported. Almost half of the patients experienced grade 3 AEs, mostly hypertension (31%) and hyperglycemia (13%), 15% had grade 4 neutropenia [51]. Currently, copanlisib is under evaluation in a Phase II trial [52]. Everolimus (RAD001) is an oral mTOR inhibitor, which has demonstrated a moderate preclinical activity on DLBCL [53]. In a Phase II trial, everolimus monotherapy induced a modest response, achieving an ORR of 30% in R/R DLBCL patients [54]. However, its antiproliferative activity appeared to increase when everolimus was combined with rituximab in DLBCL cell lines [55]. Based on these data, an open label Phase II trial was carried out to evaluate if the combination of everolimus with rituximab would also be efficacious in the clinical setting. The ORR was 38% (CR 13%, PR 25%), the duration of response was 8.1 months and at 1-year follow-up, the OS was 37%. Given the poor clinical prognosis of the patients involved in this study (R/R DLBCL patients, the majority of whom was rituximab-refractory), the results were satisfying. The combination was well tolerated but with a high rate of grade 3/4 toxicities, mainly related to myelosuppression [56]. A randomized, double-blind, Phase III trial (PILLAR-2) designed to compare the maintenance with everolimus versus placebo in high-risk DLBCL who achieved CR with first-line r-chemotherapy is ongoing [57]. B-cell receptor signaling

The B-cell receptor (BCR) is a transmembrane receptor protein located on the surface of B-cells, whose function is required for normal signal transduction and antibody production. The BCR is composed of a membrane IgM non-covalently bound to a heterodimer constituted by two immunoglobulins (Ig): Iga(CD79A)/Igb(CD79B). Stimulation of BCR induces receptor oligomerization, CD79A and B phosphorylation, the recruitment and activation of spleen tyrosine kinase, Lck/Yes novel tyrosine kinase, and thereafter Bruton’s tyrosine kinase and PI3K [58]. Aberrant activation of BCR pathway is implicated in the pathogenesis and progression of various B-cell malignancies, mainly in ABC DLBCL [59]. Novel drugs targeting various components of this pathway have been developed (FIGURE 1, TABLE 2). Fostamatinib disodium (R788) is an oral and relatively selective inhibitor of spleen tyrosine kinase. A Phase I/II study was conducted to evaluate the efficacy of this molecule in B-cell malignancies. Sixty-eight patients with NHL were enrolled in three cohorts: DLBCL, FL and other NHL (including MCL, marginal zone lymphoma and CLL). The best ORR was achieved in patients with CLL (55%, 6 of 11) and DLBCL (22%, 5 of 23). The mPFS were 6.4 and 2.7 months, respectively. Overall, the treatment was well tolerated and mild hematologic toxicities were developed [60]. Notably, all patients doi: 10.1586/14737140.2015.1009042

doi: 10.1586/14737140.2015.1009042 R/R DLBCL

Chemonaı¨ve NHL

R/R DLBCL

Chemonaı¨ve DLBCL and MCL R/R NHL

Monotherapy [64]

R-CHOP [65]

DA-EPOCH [68]

R-CHOP [69]

Monotherapy [80]

ABT-199

Apoptosis

Bcl-2 selective inhibitor

Proteasome inhibitor

44 (4)

76 (40)

44 (44)

33 (24)

70 (70)

68 (23)

77 (47) 24 (24)

61 (18)

55 (9)

Patients (n) (no DLBCL)

ORR 33% (for DLBCL) CR 11.1%

ORR 34% (for DLBCL): . ABC 83.3%, . GCB 13.3% ORR 100% (for DLBCL) CR 86%

ORR 23%: . ABC 41% . GCB 5% ORR 95% (for DLBCL): . ABC 100% . GCB 100%

ORR 22% (for DLBCL), CR 4%

ORR 30% (for DLBCL) ORR 38%, CR 13%

ORR 52.9% (for DLBCL), CR 5.8%

ORR 0% (for DLBCL)

Response rate

ABC 9.7 months GCB 3.4 months

NA

.

ABC 10.8 months GCB 3.4 months 2-year PFS 64%, 2-year OS 70%

.

OS:

NA

.

.

OS:

PFS 2.7 months

DOR 5.7 months DOR 8.1 months

NA

NA

Response duration

ABC: Activated B-cell like; BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; CR: Complete response; DA-EPOCH: Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin; DLBCL: Diffuse large B-cell lymphoma; DOR: Median duration of response; GCB: Germinal center B-cell like; mTOR: Mammalian target of rapamycin; NA: Not available; NHL: Non-Hodgkin lymphoma; ORR: Overall response rate; PFS: Progression-free survival; PI3K: Phosphoinositide-3-kinase; R/R: Relapsed/refractory; R-CHOP: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

Bortezomib

BTK inhibitor

Ibrutinib

R/R NHL

Monotherapy [60]

Spleen tyrosine kinase inhibitor

R/R NHL R/R DLBCL

Monotherapy [53] Rituximab [55]

mTOR inhibitor

Everolimus

Fostamatinib

R/R NHL

Monotherapy [50]

PI3K a and d inhibitor

Copanlisib

NF-kB pathway

BCR signaling

R/R NHL

Monotherapy [45]

PI3Kd inhibitor

Idelalisib

PI3K/AKT/mTOR pathway

Disease

Agent mechanism/ target

Trial design

Agents

Pathway

Table 2. Small molecules targeting oncogenic signaling pathways in DLBCL patients.

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Emerging drugs for DLBCL

Review

with CLL/small lymphocytic lymphoma Growth experienced an initial lymphocytosis to factors BCR B be correlated with a BCR antagonist class RTK effect. This family of drugs probably induces a disruption of signal through SYK Fostamatinib CXCR4-SDF1 and other adhesion factors RAS in the marrow and nodal sites, leading to PI3K PI3K BTK Ibrutinib inhibitors cell mobilization [61]. A Phase II trial of RAF fostamatinib in relapsed DLBCL is AKT AKT RAS MEK PKC Enzastaurin MEK inhibitors ongoing [62]. inhibitors Ibrutinib (PCI-32765) is a selective and RAD101 mTOR RAF NFKB Bortezomib ERK irreversible inhibitor of Bruton’s tyrosine IRF4 kinase, currently approved by the FDA IFN SPIB IRF7 for treatment of CLL. Ibrutinib has shown to be active also in NHL [63]. In a Phase I Lenalidomide study, the selected dose of 560 mg was well tolerated and safe. The ORR was 60% (with 16% CR) and mPFS Gene trascription 13.6 months [63]. In DLBCL, a Phase II, multicenter study was designed to evaluate the efficacy of ibrutinib. Seventy R/R DLBCL patients were enrolled. The ORR Figure 1. The key signaling pathways implicated in diffuse large B cell was 23% in all patients with a higher lymphoma with targeted novel agents in clinic development. response rate in ABC (41%) with respect BCR: B-cell receptor; PI3K: Phosphoinositide-3-kinase. to GCB DLBCL (5%; p = 0.007). The OS was longer in the ABC subtype (9.7 months) compared with the GCB (3.4 months) as well Proteasome inhibitors (p = 0.099). Response to treatment was obtained in 71% of Bortezomib is a molecule able to block NF-kB activation patients with mutant CD79B and 34% with wild-type CD79B, through proteasome inhibition [67]. Despite its weak activity as suggesting that a chronic activation of BCR increases ibrutinib single agent, when combined with chemotherapy, bortezomib sensitivity. It is noteworthy that 80% of patients with simulta- appeared to be effective in R/R DLBCL patients. Notably, the neous mutations of CD79B and MYD88 responded, but ORR and OS were higher in ABC DLBCL with respect to patients with wild-type CD79B and mutant MYD88 did not, GCB DLBCL (83 vs 13%, p < 0.001; 10.8 vs 3.4 months; suggesting a BCR-independent pathway for NF-kB activation. p = 0.003, respectively) [68]. This different response can be For the same reason, not even patients with CARD11 mutants explained by different biological mechanisms that underlie each responded [64]. Given the single-agent activity and safety, a of these diseases. Therefore, bortezomib is able to increase the Phase Ib, multicenter, non-randomized study evaluated the com- efficacy of chemotherapy in ABC DLBCL because it interrupts bination of ibrutinib with R-CHOP in previously untreated B- the aberrant activation of the NF-kB pathway [66] usually prescell NHL. Thirty-three patients were enrolled (DLBCL, n = 24; ent in this subtype, but not in GCB DLBCL. Even better MCL, n = 5; FL, n = 4). The ORR was 94% across all dose results were obtained by the combined administration of bortecohorts and 100% in patients who received ibrutinib 560 mg. zomib with R-CHOP-21 chemotherapy in untreated DLBCL. Unlike the single agent study, no difference in lymphoma sub- The ORR was 100% (CR of 86%) with 2-year PFS rate of types response was noted. Eighty-two percent of patients experi- 64% and 2-year OS rate of 70%. Unlike R-CHOP alone, the enced grade 3/4 AEs, mainly related to myelosuppression (73% combination of this regimen with bortezomib led to similar neutropenia, 21% thrombocytopenia, 18% febrile neutropenia outcomes between the GCB and ABC DLBCL subtypes [69]. and anemia). The recommended Phase II dose of ibrutinib was These results suggest that bortezomib could be able to overestablished at 560 mg once daily [65]. A Phase III trial is ongoing come the negative prognostic risks of ABC DLBCL; however, confirmative studies are required before drawing to confirm the findings of Phase I study. conclusions (TABLE 2). Several multicenter randomized trials evaluating bortezomib in combination with chemotherapy in NF-kB pathway NF-kB converges downstream of the BCR and signals through untreated [70] and R/R DLBCL [71,72] are ongoing. Toll-like receptors. Constitutive activation of the NF-kB pathway has been identified as the hallmark of ABC DLBCL and Apoptosis its disruption induces rapid cell death [66]. These findings pro- The Bcl-2 family members play a critical role in the control of cell survival through an accurate balance between proapoptotic vide a challenging target to hit (FIGURE 1). informahealthcare.com

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Review

Mondello & Younes

(Bax, Bak and BH3-only proteins) and antiapoptotic (Bcl-2, Bcl-xL, BCL-w and Mcl-1) factors. Disruption of this control leads to tumor development and progression as well as induction of chemoresistance [73]. Bcl-2 overexpression was historically considered a negative prognostic factor in DLBCL [74]; however, only when not related to translocation t(14;18), such as in ABC DLBCL [3], it is associated with a poor outcome [3,74], suggesting that the mechanism of expression plays the most important role. Nevertheless, Hu et al. demonstrated that Bcl-2 overexpression can be associated with poor prognosis only when co-expressed with MYC [75]. Because of its remarkable role and the high expression in DLBCL [3], Bcl-2 represents an attractive target for cancer therapy. Navitoclax (ABT-263) is the first-generation BH3 mimetics with inhibitory activity against Bcl-2 family members, including Bcl-2, Bcl-XL, and Bcl-w, but not Mcl-1 and A1 [76]. Although navitoclax demonstrated to be active in CLL and NHL patients, its use was limited by dose-dependent thrombocytopenia Bcl-XL related [77]. ABT-199 is a Bcl-2 selective inhibitor with 100-fold affinity for Bcl-2 over Bcl-XL. Consequently, it was associated with a minor change in platelet count [78]. Preclinical studies demonstrate a remarkable activity of ABT-199 on Bcl-2+ hematologic cancer cells. To translate these findings into the clinical setting, Souers et al. administrated ABT-199 in three R/R CLL patients as well, observing that ABT-199 induced a much greater antileukemic effect with respect to navitoclax. Less thrombocytopenia was correlated with ABT-199; however, the treatment induced rapid tumor lysis [78]. ABT-199 was evaluated also as treatment for double hit lymphoma, a particularly aggressive subtype of DLBCL characterized by overexpression of c-myc and Bcl-2. In vitro data showed a greater cytotoxic activity of ABT-199 in comparison with ABT-737. Indeed, combining ABT-199 either with chemotherapy (doxorubicin or cytarabine) or with bortezomib produced synergistic cell kill against double-hit lymphoma cells, suggesting a challenging option to use in this poor risk subtype [79]. Recently, a Phase I trial evaluated the safety and efficacy of ABT-199 in 44 R/R NHL patients. ORR was 48% with the higher response in MCL (9/12; 75%) and Waldenstro¨m macroglobulinemia (3/4; 75%). In the DLBCL group, only the highest drug dose of ABT-199 (>600 mg) induced response to treatment (3/9; 33.3%). Treatment was well tolerated and the most common grade 3 AEs were related to myelosuppression; however, thrombocytopenia was not dose-dependent [80]. Currently, Phase I/II studies evaluating the combination of ABT-199 with chemotherapy in R/R (with rituximab and bendamustine; [81]) or in newly diagnosed NHL patients (with rituximab/obinutuzumab and standard CHOP; [82]) are ongoing. Epigenomic-modifying drugs

Epigenetic mechanisms affect the regulation of gene expression independent of the primary DNA sequence. Frequently epigenetic alteration can drive cancer development and/or progression, resulting in the silencing of tumor suppressor genes, doi: 10.1586/14737140.2015.1009042

activation of oncogenes, tumor growth and metastatic progression. However, unlike genetic mutations, epigenetic changes are reversible; consequently, drugs that reinduce the epigenetic balance represent exciting potential therapeutic targets for cancer [83]. Histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACi) are epigenetic drugs that modify gene expression to restore the normal differentiation and death programs usually altered in tumor cells. Despite the large body of information, there is uncertainty about their mechanism of action [84]. Besides their ability to increase DNA acetylation that favors gene transcription, HDACi target other non-histone proteins, which may further influence cell survival [84]. Vorinostat (SAHA) inhibits mainly class I and II HDAC [85] and is approved for cutaneous T-cell lymphoma treatment. Preclinical study showed a good efficacy of vorinostat in B-cell lymphomas [86] and the results from Phase I trial were promising as well [87]; however, the Phase II trial failed [88]. In this trial, 18 R/R DLBCL patients were enrolled: seven of them received vorinostat at 300 mg twice a day. One patient achieved a CR, one a SD and the others developed progression of disease under treatment. The AEs, therapy-related, were mostly of grade 2 or less (diarrhea 61%, fatigue 50%, nausea 33%), whereas grade 3/4 thrombocytopenia and asthenia were not so common (about 15%) [88]. To increase its activity, vorinostat was evaluated within combination therapy. Preclinical data have shown a strong synergy between vorinostat and proteasome inhibitors [89]. Therefore, Dasmahapatra et al. investigated the activity of vorinostat combined with carfilzomib, a second-generation irreversible proteasome inhibitor [90]. They observed a remarkable effectiveness regardless of the DLBCL subtypes (GCB vs ABC). HDACi enhanced carfilzomib activity leading to an increased apoptosis and blockage of the NF-kB pathway [90], the principal mechanism involved in ABC DLBCL [87]. Based on these promising results, a Phase I trial was conducted in 20 R/R NHL patients (DLBCL, n = 6; FL, n = 2; MCL, n = 10 and TL, n = 2). However, the regimen did not seem really effective and the best response was 1 PR, whereas two patients remained in SD (TABLE 3) [91]. Mocetinostat (MGCD0103) is an inhibitor of class I and II HDAC, which exhibits antiproliferative activities against a broad spectrum of human cancer cell lines [92]. Although it was previously associated with several events of pericardial toxicity [93], no clear correlation was found between treatment and pericardial effusions. Recently, a Phase II trial enrolled 69 NHL patients (DLBCL, n = 41; FL, N = 28), who received mocetinostat at doses ranging from 70 to 110 mg 3-times per week every 28 days. The ORR in DLBCL and FL, respectively, was 17% (7/41) and 11% (3/28). Mean duration of SD in patients with DBLCL was 4.5 months. Overall, mocetinostat treatment appeared to be well-tolerated and safe (TABLE 3) [94]. Because DLBCL with mutation in acetylation pathways (CREBBP and EP300) has been shown to be particularly Expert Rev. Anticancer Ther.

Emerging drugs for DLBCL

Review

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Table 3. Epigenomic-modifying drugs in DLBCL patients. Pathway

Agents

Agent mechanism/target

Trial design

Disease

Patients (n) (no DLBCL)

Response rate

Response duration

HDACi

Vorinostat

Class I and II HDAC inhibitor

Monotherapy [88] Carfilzomib [91]

R/R DLBCL R/R NHL

18 (18) 20 (6)

ORR 11%, CR 5.5% ORR 15%

TTP 44 days NA

Mocetinostat

Class I and II HDAC inhibitor

Monotherapy [94]

R/R NHL

69 (41)

ORR 17% (for DLBCL)

DOR 4.5 months

CR: Complete response; DLBCL: Diffuse large B-cell lymphoma; DOR: Median duration of response; HDACi: HDAC inhibitors; NA: Not available; NHL: Non-Hodgkin lymphoma; ORR: Overall response rate; R/R: Relapsed/refractory; TTP: Time to progression.

responsive to mocetinostat, it received orphan drug designation as a treatment for DLBCL patients with this specific genetic alteration in June 2014. Bromodomain inhibitors

It is well known that MYC transcription depends on the regulatory function of BRD4 [95], a member of the bromodomain and extraterminal (BET) subfamily proteins that bind to lysine acetylated histones and promote transcription. New molecules able to inhibit bromodomain and BET protein have been shown to display anticancer activity and therefore are under study. JQ1 is the most studied BET inhibitor, which, binding BRD4, results in down-regulation of MYC and wide manipulation of gene expression [96]. JQ1 demonstrated in preclinical setting to be active in all subtypes of DLBCL leading to cell cycle arrest. Although in mouse model JQ1 induced significant growth suppression, as single agent it was not sufficient to cure the disease, suggesting the necessity to combine it with other compounds [96]. Emadali et al. associated JQ1 and rituximab, observing a reinduction of sensitivity in rituximab-resistant DLBCL cell lines [97]. Recently, JQ1 demonstrated to strongly synergize with ibrutinib in ABC DLBCL cell lines, probably because of a potent IkB kinase inhibition by BET inhibitor activity. The preclinical data showing an increased killing activity of the combination with respect to single agent in ABC DLBCL cells were also confirmed in vivo by a reduced cancer growth [98]. These findings provided the basis for clinical development of BET inhibitor in ABC DLBCL. Conclusion

Over the past decade, several important findings have provided new insights into the pathogenesis of DBCL. This has allowed designing many novel compounds targeting the main oncogenic drivers that might permit a more specific therapeutic approach in the near future. In preclinical and early clinical studies, promising results were obtained, but up to now none of the

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novel molecules has demonstrated an outstanding activity in DLBCL. However, the enrolled patients were highly pretreated and had a poor prognostic profile, which is why the results might not reflect the real efficacy of the investigated substances. Moreover, because of the frequent multipathogenetic mechanisms, monotherapy might not be an adequate approach and the combination of such agents could lead to significantly superior results. Expert commentary

Although DLBCL is a potentially curable disease, almost onethird of patients fail or relapse after first-line therapy with the identification of an increasing number of targeted agents that have promising clinical activity. The future will be to identify predictive biomarkers to select patients and to orient mechanism-based combination strategies. Five-year view

The next 5 years will focus on linking disease response and resistance to genetic and biologic biomarkers. It is imperative to start analyzing tumor samples in a comprehensive and systematic way for genetic aberrations that may predict response or resistance to a specific therapy. Because most of these new agents have a modest response rate, it is equally important to develop novel combinations based on our knowledge of the mechanism of action of these agents. Financial & competing interests disclosure

A Younes has received research support from Novartis, Johnson & Johnson and Curis. A Younes has also received honoraria from Bayer, BristolMyers Squibb, Celgene, Incyte, Janssen R&D, Sanofi, Seattle Genetics and Takeda Millenium. 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. No writing assistance was utilized in the production of this manuscript.

doi: 10.1586/14737140.2015.1009042

Review

Mondello & Younes

Key issues .

Molecular analyses identified distinct subsets of diffuse large B-cell lymphoma (DLBCL) with different underlying oncogenic processes providing an opportunity for the development of precision therapy.

.

Novel molecular antibodies against B-cell epitope (such as anti-CD20, CD-19, CD22) have been demonstrated to be more active than rituximab and are currently under evaluation.

.

Immuno-based therapy with T cells expressing a chimeric antigen receptor and antibodies anti-PD1 are emerging as new therapeutic strategies.

.

Small molecules targeting various components of PI3K/AKT/mTOR pathway have shown an antitumor activity and are currently under

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evaluation within combination treatments. .

Novel compounds targeting B-cell receptor and Bcl-2 are being tested in DLBCL with promising results. Combination strategies with front-line R-CHOP regimens are being evaluated.

.

Bortezomib and lenalidomide have shown high single agent activity in activated B-cell DLBCL, thanks to their ability to block the NF-kB pathway. Even more relevant were the results obtained combining each of these molecules with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. No difference in prognosis was revealed between activated B-cell like and germinal center B-cell like, suggesting that these two drugs are able to overcome negative risks related to DLBCL subtypes.

.

Aberrant MYC expression is a negative prognostic factor in DLBCL, therefore targeting this oncogene may result in an increased cure rate. However, reducing its expression using histone deacetylase inhibitors or bromodomain inhibitors demonstrated only a modest activity. Nevertheless, their effectiveness has proven to be significantly increased in combination with other molecules.

.

Genetic testing of tumor specimens will likely identify biomarkers that may aid in future selection of patients for therapy.

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