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New therapeutic targets and drugs in non-Hodgkin’s lymphoma Ahmed Sawas, Catherine Diefenbach and Owen A. O’Connor NYU Cancer Institute, NYU Langone Medical Center, New York, New York, USA Correspondence to Owen A. O’Connor, MD, PhD, Professor of Medicine and Pharmacology, NYU Cancer Institute, School of Medicine, Smilow Research Building, Room 1101, 522 First Avenue, New York, NY 10016, USA Tel: +1 212 263 9884; e-mail: Owen.OConnor@nyumc.org Current Opinion in Hematology 2011, 18:280–287

Purpose of review Although enormous progress has been made in treating non-Hodgkin’s lymphoma (NHL), and some patients can be cured with combination immunochemotherapy, patients with relapsed and refractory lymphoma often succumb to their disease. Advances in our understanding of lymphoma biology and molecular pathogenesis are yielding new therapeutic targets. Recent findings This article reviews NHL biology and describes how our understanding of molecular pathogenesis is leading to the discovery of many therapeutic targets, including the cell signaling and cell cycle regulatory proteins, pro-apoptotic family members, the B-cell antigen receptor (BCR), and histone deacetylase. Recent preclinical and clinical data with inhibitors of phosphatidylinositol 3-kinase, AKT, mammalian target of rapamycin, histone deacetylase, bcl-2, and the Bruton’s tyrosine kinase, a pivotal enzyme in the BCR pathway, are discussed. Summary Understanding these novel targets in the context of NHL biology will bring new therapies and allow us to develop new therapeutic platforms for the treatment of relapsed and refractory NHL, and will hopefully improve the clinical outcome for these patients. Keywords apoptosis, histone deacetylase inhibitors, Hodgkin’s lymphoma, new drugs, nonHodgkin’s lymphoma Curr Opin Hematol 18:280–287 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 1065-6251

Introduction Non-Hodgkin’s lymphoma (NHL) is the fifth most common cancer in the United States, with an increasing incidence over the past three decades [1]. Although enormous progress has been made in treating NHL, the treatments are often toxic, involving intense chemotherapy regimens and autologous or allogeneic stem cell transplant protocols. Although some aggressive forms of NHL can be cured with combination immunochemotherapy, patients with relapsed and refractory lymphoma often succumb to their disease. Therapeutic options for these patients remain limited and offer few long-term durable remissions [2]. In select forms of lymphoma, like diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), dose intense therapy followed by autologous or allogeneic stem cell transplant can cure patients with chemotherapy-resistant disease. Similarly, more dose dense regimens may be critical for effecting cure of primary mediastinal B-cell lymphoma [3], whereas others, including ACVBP (doxorubicin, cyclophosphamide, vindesine, and bleomycin) studied by the Groupe d’Etude des Lymphomes de l’Adulte (GELA), may improve the outcome of patients with DLBCL [4]. The addition of the anti-CD20 agent 1065-6251 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

rituximab to treatment combinations for both low-grade and high-grade lymphoma has significantly improved survival in B-cell NHL [5,6], leading its inclusion in standard therapy. Rituximab is paradigmatic of targeted therapies that are transforming treatment of NHL. Recent advances in our understanding of lymphoma biology and molecular pathogenesis are yielding new therapeutic targets. In this review, we will discuss how this is leading to the development of new drugs with promising therapeutic potential. At present, the number of new targets and agents is growing rapidly, making it virtually impossible to provide a comprehensive overview of all potentially relevant targets. We have limited our discussion to selected targets and pathways to illustrate the shift in our present thinking regarding the future of lymphoma developmental therapeutics (Table 1) [7–10,11,12–15,16,17,18,19,20,21,22,23].

Targeting the phosphatidylinositol 3-kinase/ AKT/mammalian target of rapamycin pathway The phosphatidylinositol 3-kinase (PI3K) pathway consists of a large family of lipid kinases that play a critical role in many cellular processes, including cell survival, DOI:10.1097/MOH.0b013e328347786d

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New targets and drugs in non-Hodgkin’s lymphoma Sawas et al. 281

cell proliferation, differentiation, and angiogenesis [24]. This pathway acts downstream of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) and is dysregulated in a number of malignancies leading to uncontrolled growth and survival [25]. Among the downstream targets of PI3K is AKT, a serine/threonine protein kinase. AKT regulates a variety of transcription factors, including nuclear factor-kB (NF-kB), which is known to regulate over 400 different genes involved in cell cycle regulation, cytokine production, and programmed cell death [26]. Mammalian target of rapamycin (mTOR) is another important component of the PI3K pathway downstream of AKT. mTOR regulates many cellular functions that include NF-kB and protein translation, and is known to play a critical role in tumorogenesis and drug resistance. mTOR activation results in capdependent protein translation, especially of cyclin-D1 and c-myc. The mTOR pathway integrates many inputs, including signals from the PI3K–AKT pathway, growth factor signaling, the energy state of the cell (cAMP levels), nutrient, and O2 availability [27].

Key points  The understanding of non-Hodgkin’s lymphoma (NHL) biology is leading to the development of many novel targeted therapies.  These therapies target functions vital to the lymphoma cells such as cell signaling, cell cycle regulation, apoptosis, and the epigenetic regulation of target genes.  Phase 1 and phase 2 clinical trials are testing a myriad of these novel compounds both as single agents and in combination with conventional chemotherapy.  Understanding the biologic mechanism, toxicity, and efficacy of these therapies will help us to develop novel treatment platforms for patients with relapsed and refractory NHL. CAL-101

PI3K inhibitor development has been limited because the pathway plays a vital role in intracellular signaling, proliferation, and differentiation. The enzyme complex is

Table 1 Novel drugs for the treatment of lymphoma

Target/agent

Phase of clinical development

Disease state

Administration

Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin CAL-101 Phase I [7] Indolent NHL Single agent MCL Phase I [8] CLL Perifosine Temsirolimus

Phase II [9] Phase II [10] Phase II [11] Phase III [12]

Everolimus

WM NHL, HL DLBCL FL CLL MCL

Single agent with sorafenib Single agent Single agent vs. investigator’s choice Single agent

Phase II [13,14]

NHL HL

BCL-2 Oblimersen

Phase II [15]

NHL

with rituximab

ABT-263 Obatoclax

Phase I [16] Phase I [17]

NHL CLL

AT-101

Phase II [18]

CLL

Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 Phase I [19,20] NHL CLL Histone deacetylase inhibitors Vorinostat Phase II [21] Romidepsin Belinostat

Phase II [22] Phase II [23]

NHL FL PTCL PTCL/ CTCL

Duration of response (months)

Response rate (mTOR) targets ORR: 62% ORR: 62% ORR: 26% and 80% had a lymph node response PR (11%) PR: 23% ORR: 28.1%; CR: 12.5% ORR: 53.8%; CR: 25.6% PR; 11% ORR: 22 vs. 2%

– 3 – 12.6 9 2.6 12.7 – 4.8 vs. 1.9

Toxicity grade 3–4

No MTD or DLT reported Cytopenia None reported None reported Cytopenia and asthenia

ORR: 30% ORR: 47%

5.7 7.2

Cytopenia

12

Cytopenia, and fatigue

Single agent Single agent

ORR: 42%; CR: 23%; SD: 28% PR: 21.7% PR: 4% n ¼ 1

with rituximab

ORR: 38%

Single agent

ORR: 43% ORR: 64%

Single agent

ORR: ORR: ORR: ORR: ORR:

Single agent Single agent

29%; 47%; 34%; 25%; 14%;

CR: CR: CR: CR: CR:

14.5% 23.5% 17%. 10% 7%

14.9 –

– 15.6 8.9 5.2 8.5

Cytopenia Infusion-related neurologic toxicity Fatigue, neutropenia and ileus Neutropenia, hypersensitivity reaction, SBO and COPD exacerbation Cytopenia and fatigue Nausea, fatigue Neutropenia and thrombocytopenia

CLL, chronic lymphocytic leukemia; COPD, chronic obstructive pulmonary disease; CR, complete response; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; FL, follicular lymphoma; HL, Hodgkin’s lymphoma; MCL, mantel cell lymphoma; MTD, maximum tolerated dose; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; PR, Partial response; PTCL, peripheral T-cell lymphoma; SBO, small bowel obstruction; WM, Waldenstrom’s macroglobulinemia.

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282 Lymphoid biology and diseases

composed of several isoforms, including a, b and d, that dimerize to create a family of different PI3 kinases, exhibiting variable expression across different cell types. Identification of the hematopoietic-selective isoform PI3K-d, and the emergence of drugs that uniquely target this isoform, has unlocked a new therapeutic opportunity for B-cell malignancies. The PI3K-d selective inhibitor CAL-101 induces apoptosis in primary chronic lymphocytic leukemia (CLL) cells ex vivo in a dose-dependent and time-dependent fashion that is independent of common prognostic markers [28]. In phase 1 studies, CAL101 was administered to 28 patients with indolent NHL [follicular lymphoma n ¼ 15, small lymphocytic lymphoma n ¼ 6, Waldenstrom’s macroglobulinemia n ¼ 4, marginal zone lymphoma (MZL) n ¼ 3] and 27 with aggressive NHL [mantle cell lymphoma (MCL) n ¼ 18, DLBCL n ¼ 9] [7]. Patients had relapsed and refractory disease with an average of five prior lines of therapy. The overall response rate (ORR) in indolent NHL was 62%, with the median duration of response not reached. In MCL, the ORR was also 62% with a median response duration of 3 months. There was no reported response in DLBCL. The main toxicities were neutropenia, lymphopenia, and thrombocytopenia. A phase I clinical trial in 54 patients with relapsed and refractory CLL reported an ORR of 26%, with 80% having a lymph node response [8]. A phase I study combining 100 mg twice daily (b.i.d.) of CAL-101 with rituximab and/or bendamustine in patients with relapsed or refractory B-cell indolent NHL and CLL is underway [29]. CAL-101 is a promising agent for combination therapy for these diseases. Future studies will explore its activity specifically in indolent NHL, CLL and MCL both as a single agent and in combination with other therapies. Perifosine

Perifosine is an AKT inhibitor with significant antineoplastic effects in human tumor cell lines. It was tested as a single agent in 37 patients with Waldenstrom’s macroglublinemia [9]. The median number of prior therapies was two. Of the 37 patients, four achieved partial response (PR) (11%), nine minimal response (24%), and 20 showed stable disease (54%). Median progression-free survival (PFS) was 12.6 months. The main adverse events were cytopenias, gastrointestinal symptoms, and arthritis flare. Preliminary results from a phase II clinical trial of the combination of perifosine and sorafenib an oral multikinase inhibitor, reported on 26 of 36 planned patients with relapsed/refractory disease (three DLBCL, three follicular lymphoma, one Waldenstrom’s macroglobulinemia, four CLL, and 15 Hodgkin’s lymphoma) [10]. Patients had a median of five prior lines of therapy. Perifosine (50 mg b.i.d.) was administered as single agent for 4 weeks to assess tolerability and tumor response. Patients achieving a response continued with perifosine alone until disease progression or limiting

toxicity. Nonresponders were given sorafanib (400 mg b.i.d.) in addition to perifosine until disease progression or limiting toxicity. The combination of sorafanib and perifosine achieved a PR of 23% with 9-month response duration. Interestingly, all responding patients had Hodgkin’s lymphoma, raising the PR rate to 33% for this histologic subgroup, suggesting that AKT inhibition may have particular relevance for Hodgkin’s lymphoma biology. Currently, perifosine is being investigated in solid tumors and in multiple myeloma, but it has potential as a targeted combination therapy in Hodgkin’s lymphoma. A registration-directed phase II study for relapsed/refractory CLL is ongoing. This drug may emerge in combination with other drugs targeting this pathway, eventually effecting complete inhibition of the PI3k/AKT/mTOR pathway. Temsirolimus

Temsirolimus is a member of the class of mTOR inhibitors, many of which are now in clinical use or in clinical trials. The first of these drugs is rapamycin (sirolimus), originally isolated from a strain of Streptomyces hygroscopicus found in the soil on Easter Island. In preclinical models, rapamycin displays potent inhibition of cell proliferation through G1 cell-cycle arrest and suppression of telomerase activity. In cutaneous T-cell lymphoma (CTCL), rapamycin suppresses cell proliferation but shows little effect on apoptosis [30]. Oral sirolimus is approved for prophylaxis against kidney transplant rejection. A phase II study evaluated weekly single agent temsirolimus 25 mg in patients with relapsed B-cell NHL [11]. Patient outcome was stratified by histology. Patients with DLBCL had an ORR of 28.1%, complete response (CR) 25.6%, median PFS of 2.6 months, and median overall survival (OS) of 7.2 months. Patients with transformed follicular lymphoma had an ORR of 53.8%, CR of 25.6%, median PFS of 12.7 months, and median OS not reached. Patients with CLL/small lymphocytic leukemia (SLL) and other indolent lymphomas had a partial response rate of 11% with no CRs. Toxicity was mainly mild and reversible. The Mayo Clinic and the North Central Cancer Treatment Group reported two clinical trials of intravenous temsirolimus for relapsed MCL [31,32]. The first phase II trial of 250 mg intravenously weekly demonstrated a 38% ORR, with a 3% CR. Hematological toxicity was significant. A follow-up study with a similar design tested low-dose temsirolimus (25 mg weekly) for patients with relapsed MCL. Of 29 patients enrolled, 28 were evaluable for toxicity and 27 for efficacy. Patients had received a median of four prior therapies and 50% were refractory to their last treatment. The ORR was 41% with one patient achieving CR (3.7%). The median time to progression (TTP) in all patients was 6 months. Thrombocytopenia was the most frequent cause of dose reduction. A recently completed phase III trial randomized patients with relapsed MCL to

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New targets and drugs in non-Hodgkin’s lymphoma Sawas et al. 283

one of two schedules of temsirolimus vs. single-agent treatment of the investigator’s choice [12]. Treatment with temsirolimus 175/75 mg compared to the investigator’s choice resulted in improved PFS (4.8 vs. 1.9 months) and ORR (22 vs. 2%) and a trend toward longer OS (12.8 vs. 9.7 months). The most frequent adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. These data suggest that mTOR inhibition may be a viable target for directed therapy in relapsed MCL and large cell NHL. Everolimus

Everolimus is an oral derivative of temsirolimus approved for the treatment of advanced kidney cancer. A phase II clinical trial of single agent everolimus at 10 mg daily in 77 patients with relapsed/refractory aggressive NHL [13] showed an ORR of 30%, with three patients achieving a CR. The ORR in DLBCL was 30%, MCL was 32%, and in grade 3 follicular lymphoma was 38%. The median duration of response was 5.7 months. Adverse effects included anemia, neutropenia, and thrombocytopenia. It was concluded that everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway has clinical efficacy. The same trial included 17 patients with relapsed Hodgkin’s lymphoma [14]. They had a median of six prior therapies and 82% had a prior stem cell transplant (SCT). The ORR was 47%. Early analysis from this phase II study shows that oral everolimus has promising single-agent activity with good tolerability in bortezomib-refractory and intolerant MCL [33]. There are several studies evaluating everolimus’ role as a single agent or in combination in CLL, MCL, and multiple myeloma. The results with both temsirolimus and everolimus in NHL and Hodgkin’s lymphoma provide proof-of-concept that targeting the mTOR pathway in lymphoma has potential therapeutic efficacy. The greatest potential for these agents will be in combination with other conventional and novel therapies. Synergistic activity between mTOR inhibitors has been demonstrated in combination with doxorubicin, vincristine, and bortezomib [30]. In preclinical data, everolimus is synergistic with gemcitabine or paclitaxel in six NHL cell lines [34]. Gemcitabine and paclitaxel induced caspase-dependent apoptosis in association with downregulation of mTOR signaling [34]. Rapamycin and its analogues (rapalogs) also inhibit mTORC1, one of two forms of the mTOR enzyme in the cell. This may decrease the activity of these inhibitors through incomplete suppression of the pathway or upregulation of upstream targets such as AKT. A new class of small molecules targeting the ATP-binding site of the TOR kinase, termed active-site TOR inhibitors (asTORi), achieves greater inhibition of both TOR com-

plexes, resulting in broader suppression of the PI3K/ AKT/TOR signaling network. Preclinical evidence suggests that asTORi have greater efficacy than rapalogs in Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) and in T-cell lymphoma. These agents are better tolerated in animal models relative to rapalogs or inhibitors of PI3K [35]. Examples of these novel agents include LY294002, which reduced the ability of acute myelogenous leukemia (AML) cells to engraft in immunocompromised mice [36]. mTOR inhibitors will likely emerge in combination with other small molecules as active combinations in the treatment of relapsed and refractory lymphoma.

Targeting BCL-2 The BCL-2 family of proteins consists of three discrete families, including the pro-apoptotic proteins (BAX/ BAK,) the antiapoptotic proteins (BCL-2, MCL-1, etc.) and the BH3 only proteins (bim, bid, puma, NOXA, etc.). These proteins regulate the cellular balance between survival and programmed cell death. Overexpression of BCL-2 is common in NHL and associated with poor response to therapy and shorter survival [37]. Cancer cells harboring amplifications of MCL1 and BCL2 depend upon expression of these genes for survival [38]. Rituximab can overcome chemotherapy failure in DLBCL patients with BCL-2 protein overexpression [39]. A study of rituximab-induced apoptosis in human B-cell NHL models demonstrated that Bcl-xL expression confers resistance to rituximab-induced apoptosis in vitro and rituximab treatment of xenografted B-cell NHL in vivo. Overexpression of BCL-2 has been demonstrated to render B-cell NHL and cutaneous B-cell lymphoma resistant to rituximab-induced apoptosis [40,41]. The growing understanding of the role of the BCL-2 proteins in regulating apoptosis has sparked investigation of whether modulation of BCL-2 family gene expression and function can enhance the antitumor effects of conventional chemotherapeutic agents and biologic agents. Oblimersen

The BCL-2 antisense molecule oblimersen is an 18-base, single-stranded phosphorothioate oligonucleotide that targets BCL-2 mRNA. This results in recruitment of RNAse H, which degrades tBCL-2 mRNA. Loss of BCL-2 protein results in cell death by apoptosis through the caspases pathway, autophagy by disruption of the interaction between BCL-2 and Beclin-1, or by a nonantisense effect that results in an immune-mediated response [42]. Oblimersen had limited efficacy in phase I trials in NHL [43]. The agent performed better in combination with rituximab in relapsed/refractory B-cell NHL patients [15]. In a phase II trial, oblimersen was administered by continuous intravenous infusion for 7 days every other week in combination with rituximab

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284 Lymphoid biology and diseases

given weekly for 6 weeks. Patients with stable disease or objective response could receive a second course of treatment. The ORR was 42% with 55% CR. Two of the responses (one CR and one PR) were observed in rituximab-refractory patients. The median duration of response was 12 months. Adverse effects included cytopenias and fatigue. Perhaps the most encouraging results came from a phase III trial involving relapsed refractory CLL patients [44]. Patients were randomized to fludarabine/cyclophosphamide with or without oblimersen. The oblimersen arm demonstrated superior ORR and 5-year median OS [45]; however, the Food and Drug Administration (FDA) requires a confirmatory trial prior to approval. Despite the encouraging results of the combination, this agent’s development in lymphoma has been limited. ABT-263

ABT-263 is a novel, orally bioavailable BH3 BAD like mimetic that binds and inhibits several BCL-2 family members [46]. Fifty-five patients with relapsed lymphoid malignancies were enrolled in a phase I study (DLBCL six, MCL four, follicular lymphoma 16, CLL 20) [16]. The ORR was 21.7% with a median PFS of 14.9 months. The most significant toxicities were thrombocytopenia, lymphocytopenia, and neutropenia. Subsequently, a 150 mg 7day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 trial. Preliminary results from a phase I study combining ABT-263 with rituximab in 12 NHL patients with relapsed and refractory disease demonstrated an ORR of 67% with a CR 33.3% [47]. ABT-263 is also being studied in combination with fludarabine/cyclophosphamide/rituximab vs. bendamustine/rituximab alone in NHL [48], and in solid tumors such as lung cancer. However, preclinical models have identified resistance to this compound in lymphoma cell lines that upregulate MCL-1 and BFL-1 [49]. ABT-263 is one of the most promising agents targeting this biology in development, but thrombocytopenia may limit its development. Obatoclax

Obatoclax was discovered in a high-throughput screen for natural compounds that disrupt Bcl-2 family protein– protein interactions [50]. In vitro, obatoclax acts as a BH3-bim mimetic and binds to antiapoptotic Bcl-2 family members: Bcl-2, Bcl-XL, Bcl-w, and Mcl-1. In a phase 1 study of q3-weekly intravenous obatoclax in 26 patients with relapsed CLL, one patient achieved a PR, and 18 patients experienced reductions in lymphocyte count, with a mean reduction of 29% [17]. Dose-limiting toxicities included treatment-related neurologic events such as somnolence, ataxia, and dysphoria. No significant hematologic toxicity was reported. A phase II study of combination obatoclax and bortezomib in 12 patients with relapsed/ refractory MCL yielded an observed ORR of 25% and CR of 25% [51]. This agent is being studied in CLL, MCL,

multiple myeloma, acute myeloid leukemia (AML), myelodysplastic syndromes (MDSs), and lung cancer. Preclinical data in acute lymphocytic leukemia (ALL) cell lines suggest synergy with ABT-737, a BH3 BAD like mimetic closely related to ABT-263 [52]. Preclinical studies of this combination in vivo are planned. AT-101

AT-101 is a derivative of the natural compound gossypol, a cottonseed extract (Gossypium sp.). It has been used as an antifertility agent and as a cytotoxic agent. AT-101 is a BH3 only mimetic known to be a potent inhibitor of Bcl-2 family members, including Bcl-2, Bcl-X(L), and Mcl-1 [53]. In vitro, AT-101 enhances the activity of cytotoxic agents in lymphoma and multiple myeloma cell lines [54]. AT-101 is synergistic with carfilzomib, etoposide, doxorubicin, and 4-hydroxycyclophosphamide (4-HC) in MCL lines. In a transformed large B-cell lymphoma line, AT-101 was synergistic when sequentially combined with 4-HC. AT-101 also induced mitochondrial membrane depolarization and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. The addition of AT-101 to cyclophosphamide and rituximab in a schedule-dependent manner enhanced the efficacy of the combination in MCL and DLBCL cell lines [53]. In a phase II clinical trial, 12 patients with relapsed/ refractory CLL received AT-101 continuously in combination with rituximab, achieving an ORR of 38% [18]. A similar study of six patients receiving pulsed AT-101 reported ORR of 50% [55]. Intermittent dosing compared with continuous dosing increases the pro-apoptotic effect in vivo, with higher plasma concentrations, and reduced toxicity. There is an ongoing study of AT-101 combined with lenalidomide for relapsed and refractory CLL.

Targeting Bruton’s tyrosine kinase B-cell antigen receptor (BCR) has been shown to play an important role in the survival and maturation of B cells. The Bruton’s tyrosine kinase (BTK) is pivotal for the BCR pathway. BTK mutations in humans cause inherited X-linked agammaglobulinemia, characterized by absence of peripheral B cells and depressed serum immunoglobulins. Chronic activation of the BCR pathway has been demonstrated in some NHLs, and this activation is required for tumor cell survival [56]. Thus, BTK has emerged as a new antiapoptotic molecular target for the treatment of B-lineage leukemias and lymphomas. PCI-32765

PCI-32765 is an oral, potent, and selective covalent inhibitor that binds irreversibly to BTK, is orally available, and is effective with once daily dosing. It blocks BCR signaling and inhibits tumor growth in both murine and canine NHL models. PCI-32765 is undergoing clinical development in patients with B-cell malignancies

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New targets and drugs in non-Hodgkin’s lymphoma Sawas et al. 285

and has promising clinical activity [57]. A phase I study of 47 patients with B-cell malignancies (CLL 15, follicular lymphoma 15, DLBCL eight, MCL four, and MZL three) reported an ORR of 43% [19]. The major adverse events were neutropenia, hypersensitivity reaction, small bowel obstruction, and exacerbation of chronic obstructive pulmonary disease. Another study evaluating this agent in CLL/SLL included patients with refractory/ relapsed disease as well as treatment-naive elderly patients [20]. Preliminary results indicate ORR of 64% with 86% of the patients experiencing nodal response. This promising agent is being investigated in NHL, CLL, and MCL, and studies in combination with immune-chemotherapy and traditional chemotherapeutic agents are also underway.

Romidepsin

Romidepsin is a novel potent bi-cyclic HDACi, also FDA approved for CTCL, that has been investigated mainly in multiple myeloma and T-cell lymphoma. A phase II trial of 47 patients with relapsed or refractory PTCL of various subtypes, including PTCL not otherwise specified (NOS), angioimmunoblastic and ALK-negative anaplastic large cell lymphoma [22] demonstrated an ORR of 34% and a CR of 17% with a median duration of response of 8.9 months. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. The agent is also being investigated in combination therapy in B-cell NHL and multiple solid tumors, including lung cancer, head and neck cancer, and renal cancer. Belinostat

Histone deacetylase inhibitors Histones are DNA-binding proteins. Like many other proteins, they are affected by posttranscriptional modifications such as acetylation by histone acetyltransferases (HATs). This modification dissociates the histone:DNA interaction, facilitating transcription. Histone deacetylase inhibitors (HDACis) are thought to exert their action by modulating gene expression in a wide variety of tumor types. HDACis increase expression of cell cycle regulators, cell type specific differentiation genes, tumor antigens, and genes encoding proapoptotic proteins [58,59]. In addition, many nuclear and cytoplasmic proteins undergo acetylation, suggesting that HDACis may have additional antitumor effects that are separate from modulation of gene expression [60]. Vorinostat

Suberoylanilide hydroxamic acid (SAHA) is an orally administered hydroxamic acid HDACi with activity against class I and II deacetylases. It is approved for the treatment of CTCL with reported preclinical and clinical activity against various forms of lymphoma. A phase II clinical trial of patients with relapsed/refractory follicular lymphoma, MZL, and MCL [21] reported an ORR of 29% and CR rate of 14.5%. For patients with follicular lymphoma, ORR was 47% and CR was 23.5%. There were no responders among MCL patients. The median PFS was 15.6 months for follicular lymphoma patients, 5.9 months for MCL patients, and 18.8 months for MZL patients. The most common adverse events were thrombocytopenia, anemia, leukopenia, and fatigue. A similar phase II trial with the combination of vorinostat and rituximab is underway [61]. In 17 evaluable patients, ORR is 35% and CR is 29%. In follicular lymphoma patients, ORR is 43%. The median PFS has not been reached. It seems that vorinostat may be especially active in follicular lymphoma. It is also being studied in combinations with traditional chemotherapy in DLBCL, multiple myeloma, leukemia, and myelodysplasia.

Belinostat is another hydroxamic acid pan-HDACi that is being evaluated in solid tumors and hematologic malignancies. An ongoing phase I trial in patients with relapsed or refractory lymphoma, with an average of five prior therapies, showed a single CR out of 16 patients evaluable for efficacy [62]. The patient had Hodgkin’s lymphoma and achieved a CR after two cycles of therapy and was treated with additional two cycles. A phase II trial of belinostat in relapsed/refractory T-cell lymphomas included 21 PTCL patients and 29 CTCL patients [23]. In PTCL, the ORR was 25% and the CR was 10% in 20 evaluable patients with a median duration of response of 5.2 months. For the CTCL, all patients were evaluable, the ORR was 14%, and the CR was 7% with a median duration of response of 8.5 months. The significant toxicities include neutropenia and thrombocytopenia.

Conclusion This review introduces several novel targeted strategies emerging in clinical trials for the treatment of lymphoma. The increasing understanding of the genomics and proteomics of lymphoma biology has allowed the development of new agents against established targets, such as the new anti-CD20 agent ofatumumab. It has also allowed the elucidation of novel therapeutic targets. In the forthcoming years, clinical trials will utilize these novel therapeutics as single agents or in combination regimens to maximize efficacy, maintain quality of life, and minimize toxicities.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 306). 1

Zelenetz AD, et al. NCCN Clinical Practice Guidelines in Oncology: nonHodgkin’s lymphomas. J Natl Compr Canc Netw 2010; 8:288–334.

2

Rogers BB. Overview of non-Hodgkin’s lymphoma. Semin Oncol Nurs 2006; 22:67–72.

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286 Lymphoid biology and diseases 3

Hamlin PA, Portlock CS, Straus DJ, et al. Primary mediastinal large B-cell lymphoma: optimal therapy and prognostic factor analysis in 141 consecutive patients treated at Memorial Sloan Kettering from 1980 to 1999. Br J Haematol 2005; 130:691–699.

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Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7:379–391. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–3732. Kahl B, Byrd JC, Flinn IW, et al. Clinical safety and activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, in patients with relapsed or refractory non-Hodgkin lymphoma [abstract]. ASH Annual Meeting Abstracts 2010; 116:1777. Furman RR, Byrd JC, Brown JR, et al. CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110{delta}, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory chronic lymphocytic leukemia [abstract]. ASH Annual Meeting Abstracts, 2010; 116:55. Ghobrial IM, Roccaro A, Hong F, et al. Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/ refractory Waldenstrom’s macroglobulinemia. Clin Cancer Res 2010; 16:1033–1041.

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13 Witzig TE, Reeder CB, Laplant BR, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia 2011; 25:341–347.

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14 Johnston PB, Inwards DJ, Colgan JP, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol 2010; 85:320–324.

32 Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005; 23:5347–5356.

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33 O’Connor OA, Popplewell L, Winter JN, et al. PILLAR-1: preliminary results of a phase II study of mTOR inhibitor everolimus in patients with mantle cell lymphoma (MCL) who are refractory or intolerant to bortezomib [abstract]. ASH Annual Meeting Abstracts 2010; 116:3963.

16 Wilson WH, O’Connor OA, Czuczman MS, et al. Navitoclax, a targeted high affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 2010; 11:1149–1159. This phase 1 study elucidates the toxicities (thrombocytopenia and lymphopenia) and establishes a phase 2 dose and schedule for navitoclax in patients with lymphoid malignancies.

34 Chiang CT, Yeh PY, Gao M, et al. Combinations of mTORC1 inhibitor RAD001 with gemcitabine and paclitaxel for treating non-Hodgkin lymphoma. Cancer Lett 2010; 298:195–203.

17 O’Brien SM, Claxton DF, Crump M, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 2009; 113:299–305. 18 Castro JE, Olivier LJ, Robier AA, et al. A phase II, open label study of AT-101 in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia [abstract]. ASH Annual Meeting Abstracts 2006; 108:2838.

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New Therapeutic Targets and Drugs in non-Hodgkin's Lymphoma  

Current treatment pipeline for NHL

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