Review

New drugs for aggressive B-cell and T-cell lymphomas

Niels Murawski, Michael Pfreundschuh
Lancet Oncol 2010; 11: 107485 Saarland University Medical School, Homburg, Germany (N Murawski MD, Prof M Pfreundschuh MD) Correspondence to: Prof Michael Pfreundschuh, Klinik fr Innere Medizin I, Saarland University Medical School, D-66421 Homburg (Saar), Germany michael.pfreundschuh@uks.eu

Over the past decade an unprecedented number of new drugs for lymphomas have been developed. Most of these new drugs target molecules or pathways that are important for the growth and proliferation of lymphomas. The introduction of the B-lymphoma specic monoclonal anti-CD20 antibody, rituximab, has improved the prognosis of patients with B-cell lymphomas more than any other drug in the past 50 years; today less than half of the patients with aggressive B-cell lymphomas die of their disease than in the pre-rituximab era. Many new drugs are now available for clinical testing in addition to new CD20 antibodies and antibodies directed against other surface molecules specically or preferentially expressed on the lymphoma-cell surface. A prerequisite for the development of these drugs was the recognition of aberrant cell-signal transduction involved in lymphoma pathogenesis and progression. New therapeutic targets include receptor tyrosine and cyclin-dependent kinases, histone deacetylases, and molecules involved in the regulation of apoptosis. The denition of the role of these new drugs alone or in combination with established chemotherapy regimens in adequately designed prospective trials represents one of the major challenges in clinical lymphoma research.

Introduction
Lymphoma, the fth most common cancer, is becoming more common in developed countries where 90% are derived from B cells and 10% from T cells. The WHO classication1 describes clinicopathologic lymphoma entities on the basis of morphological, immunological, genetic, and clinical characteristics. Of the many new drugs developed for lymphomas our review will focus on the subset that has been clinically assessed, and we necessarily omit those molecules that are still in preclinical testing.

gemcitabine and oxaliplatin is eective in relapsed DLBCL and well tolerated by patients not t enough to undergo high-dose chemotherapy and stem-cell transplantation.3,4 The experience with other cytotoxic drugs in DLBCL is too limited to allow for any estimation of their future role in aggressive lymphomas.

Antibodies
There are many new antibodies for the treatment of aggressive lymphomas: CD20 antibodies, antibodies targeting antigens other than CD20, radionuclideconjugated antibodies, toxin-conjugated antibodies, bispecic antibodies, and chimeric antigen receptor constructs. Rituximab is a monoclonal chimeric (mouse and human) antibody that targets the CD20 antigen on the surface of normal B-cells and malignant cells of CD20 B-cell lymphomas. The addition of rituximab to CHOP or CHOPlike regimens has reduced the DLBCL-associated deaths of young and old patients to less than half of what was reported 10 years ago5,6 without a relevant increase of toxic eects. The toxic eects of rituximab are mild and usually limited to the rst application when there might be dyspnoea and fever, which are usually self-limited and resolve upon the reduction of infusion velocity. Other sideeects of rituximab include herpes simplex virus stomatitis and an increase in herpes zoster. Second-generation anti-CD20 antibodies are not chimeric, but humanised or primarily human antibodies. By contrast with type-I (rituximab-like) anti-CD20 antibodies, type-II (tositumomab-like) antibodies do not induce a translocation of the CD20 molecule in the lipid rafts. Type II antibodies have a stronger complementdependent cytotoxicity and have stronger direct eects on B-cells. Examples of new type-I CD20 antibodies are ofatumumab, ocrelizumab,7 AME-133, PRO131921, and veltuzumab8 (table 2)10. The range of side-eects is similar to that of rituximab. Ofatumumab is eective in relapsed or refractory follicular lymphoma13 and chronic lymphocytic leukaemia,14 for which it was recently approved by the US Food and Drug Administration (FDA) and European
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Aggressive B-cell lymphomas

The combination of the anti-CD20 antibody rituximab with the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard treatment, accepted worldwide, for diuse large B-cell lymphomas (DLBCL), which include 3040% of non-Hodkgin lymphomas (NHL). By gene expression studies three subtypes of DLBCL have been identied: the activated B-cell-like DLBCL, the germinal centre-like DLBCL, and the mediastinal large B-cell lymphoma. Activated B-cell-like and germinal centre-like DLBCL dier with respect to the cell of origin, pathogenetic mechanisms, and prognosis. Increasing knowledge about pathogenetic pathways forms the basis for the development of drugs that target molecules involved in signal transduction, apoptosis, and dierentiation.

Cytotoxic drugs
There are many new cytotoxic drugs for the treatment of aggressive lymphomas. Bendamustine is approved for indolent lymphomas and in some countries for chronic lymphocytic leukaemia and multiple myeloma, although its role in the treatment of aggressive lymphomas has not been established (table 1). Pixantrone, which lacks the 5,8-dihydroxy substitution groups thought to be responsible for the cardiac toxicity associated with mitoxantrone, was superior to the investigators choice as third-line therapy for aggressive lymphomas2 and is now being tested in earlier indications. The combination of
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Specication AZD4877 Bendamustine Combretastatin Clofarabine Daniquidone (batracylin) Darinaparsin Dimethane sulfonate (DMS612) FAU Fenretinide Gemcitabine GS-9219 LMP400, LMP776 Nelarabine Oxaliplatin Pixantrone Pralatrexate SB-743921 Specic potent inhibitor of kinesin spindle protein Alkylating agent Tubulin-binding vascular disruptive agent Second-generation purine nucleoside Inibitor of topoisomerase I and II Small-molecule organic arsenical Alkylating agent 2-F-ara-deoxyuridine prodrug Synthetic phenylretinamide analogue of retinol Anti-metabolite deoxynucleoside analogue Prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine Indenoisoquinolones Arabinonucleoside antimetabolite Organoplatinum complex Non-cardiotoxic aza-anthrazenedione Folate analogue inhibitor of DHFR

Eligibility Solid tumours, lymphomas Aggressive lymphomas, mantle-cell lymphoma Advanced solid tumours Lymphoma Peripheral T-cell and natural-killer-cell lymphoma Solid tumours, lymphomas Advanced lymphomas Advanced malignancies Solid tumours, lymphoma B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma Non-Hodgkin lymphoma, chronic lymphocytic leukaemia, multiple myeloma Solid tumours, lymphomas T-cell lymphoma Lymphoma Lymphoma third-line Peripheral T-cell lymphoma

Phase 1/2 1/2 1

NCT trial number* NCT00471367 NCT0958256, NCT00891839 ..

Supplementary webreferences .. 1 2 3 .. 4 .. ..

1 and 1/2 NCT0064418, NCT00156013 2 .. 1 1 1 1 1/2 1/2 2 1 1 2 2 2 2 NCT00450502 NCT00591422 NCT00923520 NCT00769288

NCT00288067, NCT00104923 .. NCT00863369, NCT00481871 .. NCT00499239 NCT01051635 NCT00005950 NCT01019863 NCT0088530 NCT00998946 NCT00343564 .. .. .. .. 5 6 7

Small molecule inhibitor of kinesin spindle protein Lymphoma

*NCT trial number: for trial registered with ClinicalTrials.gov, see http://www.ClinicalTrials.gov. See webappendix for these references. Refractory and relapsed.

Table 1: New cytotoxic drugs for aggressive lymphomas

Medicines Agency, but results in DLBCL are not yet available. GA-101, a third-generation, humanised, and glycoengineered CD20 IgG1 type-II antibody has increased antibody-dependent cytotoxicity compared with rituximab, partly due to enhanced binding to FcRIIIa.9 If and which of the new CD20 antibodies will eventually displace rituximab in the treatment of DLBCL remains to be seen. The more eective clearing of B cells from lymph nodes by these new CD20 antibodies in preclinical models could translate into more substantial immunosuppression in patients and higher rates of infection. CD22 is unique in that it is internalised into cells when bound by antibody, making it an interesting target for radioimmunotherapy and antibody-toxin conjugates. Epratuzumab, a humanised antibody against CD22 deals with the problem of heterogeneous CD20 expression on DLBCL cells. Side-eects are most pronounced on rst exposure and consist of vomiting, dyspnoea, nausea, back pain, upper respiratory tract infection, diarrhoea, and cough. A combination of rituximab and epratuzumab in patients with DLBCL achieved a response rate of 67%, which was higher than that reported for either antibody alone.15 However, in combination with CHOP the epratuzumabrituximab cocktail was not better than rituximab with CHOP (R-CHOP) in untreated patients with DLBCL, although neutropenic fever grades 3 and 4 were more common. Galiximab is directed against CD80, a member of the B7 ligand family. CD80 is a costimulatory molecule
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involved in the regulation of T cells and normal and malignant B cells. Galiximab blocks the costimulating interaction between CD28 and CD80. Common sideeects are fatigue, nausea, headache, and rare cytopenias. Clinical experience with galiximab alone or in combination with rituximab in DLBCL is limited.10 CD40 agonists enhance antigen presentation, break tolerance, bypass T-cell help, and induce apoptosis in CD40-positive cells. SGN-40 (dacetuzumab), an agonistic anti-CD40 antibody was active in early trials of B-cell lymphomas and multiple myeloma.16 Fatigue, pyrexia, and headache were the most common side-eects. Four responses were recorded in 21 patients with DLBCL, including two complete responses which persisted more than 4 months;17 however, a placebo-controlled phase-2b trial was discontinued because the intended superior response was not met. Mapatumumab is an agonistic monoclonal antibody that targets the tumour necrosis factor-related apoptosisinducing ligand receptor TRAIL-R1, and lexatumumab targets TRAIL-R2, thereby activating the extrinsic celldeath pathway, which induces apoptosis. Mapatumumab is well tolerated, with fatigue, nausea, anorexia, and abdominal pain being the most common adverse reactions. TRAIL antibodies had only minor ecacy as single agents. However, because of their synergistic activity with several cytotoxic drugs in vitro, mapatumumab,18 lexatumumab,19 and conatumumab11 are now being clinically evaluated in combination with conventional chemotherapy.

See Online for webappendix

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Specicity Siplizumab Zanolimumab Blinatumomab Ofatumomab Veltuzumab Ocrelizumab AME-133 PRO131921 GA 1019 Epratuzumab Lumiliximab Dacetuzumab HCD122 TAK-901 131I BC8 Alemtuzumab hLL1 Milatuzumab Galiximab Ipilimumab Tremelimumab CT-011 Cixutumumab AMG 479 MK-0646 Bevacizumab Mapatumumab Lexatumumab Conatumumab11 KW-076112 CD2 CD4 CD19/CD3 bispecic monoclonal antibody CD20, more cytotoxic type-I monoclonal antibody CD20, Fc-engineered type-I monoclonal antibody CD20, increased anity type-I monoclonal antibody CD20, increased ADCC type-I monoclonal antibody C20, glyco-engineered type-II monoclonal antibody CD22 CD23 CD40 agonist CD40 agonist Fully human anti-CD40 monoclonal antibody CD45 CD52 CD74 CD74 CD80 CTLA-4 CTLA-4 PD-1 (B7 receptor family) Insulin-like growth factor receptor Insulin-like growth factor receptor Insulin-like growth factor-1 Anti-VEGF TRAIL receptor-1 agonist TRAIL-R2 (death receptor 5) TRAIL-R2 agonist CCR4

Eligibility T-cell and natural-killer-cell non-Hodgkin lymphoma Peripheral T-cell lymphoma (orphan drug) B-cell non-Hodgkin lymphoma Diuse large B-cell lymphoma B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma CD20 lymphoma Naive diuse large B-cell lymphoma Chronic lymphocytic leukaemia Diuse large B-cell lymphoma Non-Hodgkin and Hodgkins lymphoma Haematological malignancies Lymphoma T-cell and natural-killer-cell lymphomas B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma Solid tumours and lymphoma Solid tumours and lymphoma Advanced cancer Solid tumours and lymphoma Solid tumours Naive diuse large B-cell lymphoma Advanced malignancies Solid tumours, lymphoma Lymphoma Adult T-cell leukaemia; peripheral T-cell lymphoma

Phase 1 2 1/2 2 1/2 1/2 1/2 1/2 2 2 1/2 2 1/2 1 1 1 1/2 1/2 1/2 1 1/2 1 1/2 1 3 1/2 1 1/2 2

NCT trial number* NCT00832936 NCT00274742 NCT01078922 NCT00112970 NCT00354926 NCT00452127 NCT00517530 NCT00670592 NCT00807677 NCT00860171 NCT00504972 NCT00989586 NCT00556881 NCT00532259 NCT00678769 NCT00486759 NCT00428272 NCT0888927

Supplementary webreferences .. 8 .. .. 9 .. .. 10 11 12 13,14 15 .. .. .. .. 16 .. .. 17 .. .. 18 19 .. 20 .. 21 22

CD20, subcutaneous formulation type-I monoclonal antibody B-cell non-Hodgkin lymphoma

NCT00323323, NCT00646854 ..

*NCT trial number: for trial registered with ClinicalTrials.gov, see http://www.ClinicalTrials.gov. See webappendix for these references. Refractory and relapsed.

Table 2: New monoclonal antibodies for aggressive lymphomas

For the trials referred to in this review see http://www. ClinicalTrials.gov/

Bevacizumab binds vascular endothelial growth factor (VEGF) and is approved for the treatment of several solid tumours. Common side-eects include hypertension, proteinuria, thromboembolism, impaired wound healing, and bleeding. DLBCL often cause substantial neoangiogenesis; in particular DLBCL with a stromal-2 signature might be sensitive to inhibition of neoangiogenesis.20 However, the MAIN trial (NCT00486759), which compared R-CHOP with R-CHOP plus bevacizumab for untreated DLBCL was stopped early because of an amplied number of cardiac toxic eects and apparent lack of benet. Activation of T lymphocytes needs two signals, one delivered by the T-cell receptor complex after antigen recognition and one provided on engagement of costimulatory receptorseg, CD28. Opposing inhibitory signals, such as those delivered by cytotoxic T-lymphocyte antigen 4 (CTLA4), modulate the immune response and

increase the threshold for T-cell activation. Blockade of CTLA4 by anti-CTLA4 monoclonal antibodies enhances T-cell antitumour responses. Phase 1/2 clinical trials with ipilimumab in patients with various malignancies showed that ipilimumab was safe and provided evidence of its antitumour eects, notably in a randomised trial of advanced melanoma, where it substantially prolonged survival compared with a gp100 vaccine.21 In a phase 1/2 study in relapsing and refractory lymphomas, one of three patients with DLBCL responded to ipilimumab including complete remission for longer than 31 months.22 Table 2 lists other antibodies assessed in patients with non-Hodgkin lymphoma. Two radionuclide-conjugated anti-CD20 antibodies have been approved for follicular lymphoma: I-tositumomab (in the USA only) and Y-ibritumomab tiutexan. Toxic eects are primarily haematological, with nadir counts at 79 weeks and lasting 14 weeks. The risk
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of haematological toxic eects increases with the degree of bone marrow involvement; therefore radionuclideconjugated anti-CD20 antibodies should not be given to patients with substantial bone marrow inltration by lymphoma cells. In a phase 2 study of relapsed and refractory DLBCL, Y-ibritumomab tiuxetan was safe and ecacious in rituximab-naive patients, but the response rate in patients who had rituximab as part of their primary treatment was only 19%, with 12% complete response or complete response uncertain. In a phase 2 trial of CHOP chemotherapy which preceded Y-ibritumomab tiuxetan in previously untreated elderly patients with DLBCL, a 2-year progression-free survival of 75% and an overall survival of 95% were recorded.23 Encouraging results were also reported for high-risk elderly patients who received sequential R-CHOP and Y-ibritumomab tiuxetan.24 Several phase 2 trials have shown promising results with high-dose radioimmunotherapy as a myeloablative regimen before autologous stem-cell transplantation, standard-dose radioimmunotherapy plus high-dose chemotherapy, or high-dose radioimmunotherapy plus high-dose chemotherapy in relapsed DLBCL.25 However, with rituximab serum concentrations detectable until 9 months after the last application and its higher anity to the CD20 molecule, we do not expect radiolabelled CD20 antibodies to play a relevant part in the future treatment of DLBCL. This also applies to a radiolabelled CD22 antibody, which showed a 50% response in a small study with relapsed or refractory DLBCL.26 Antibody-toxin conjugates consist of an antibody attached to a toxic drug via a linker, and are used to deliver toxic drugs selectively to malignant cells with a surface antigen that corresponds to the antibody. The only approved toxin-antibody conjugates are gemtuzumab
Specicity UCHT1 EMD 521873 DT2219ARL SAR3419 DI-Leu-IL-2 CAT-8015 Brentuximab vedotin Inotuzumab ozogamicin Denileukin ditox28,29 MDX-1203 SGN-75 CD19CAR-zeta Alefacept CD3 CD8 CD19/CD22 CD19 CD20 CD22 CD30 CD22 CD25 CD70 CD70 CD19 LFA3 Conjugate/toxin Diphtheria toxin Interleukin 2 Diphtheria toxin Maytansinoid DM4 Interleukin 2 Pseudomonas toxin Monomethyl-auristatin E Calicheamycin Diphtheria toxin Rachelmycin Monomethyl auristatin F T-cell receptor LFA/IgG fusion protein

ozogamicin for CD33-positive relapsed acute myeloid leukaemia and denileukin diftitox for persistent or recurrent cutaneous T-cell lymphoma (TCL). A CD22 antibody conjugated to pseudomonas toxin is in early clinical trials (NCT00515892). Inotuzumab ozogamicin (CMC-544) is an anti-CD22 antibody conjugated to calicheamycin, a potent antitumour antibiotic that binds DNA and causes double-strand breaks resulting in apoptosis. In phase 1/2 studies the main adverse events were haematological, in particular reversible thrombocytopenia. Six of 14 patients with DLBCL had a complete response with an inotuzumab ozogamicin (CMC-544) rituximab combination.27 Table 3 lists other new antibodytoxin conjugates. Bispecic T-cell engaging (BiTe) antibody constructs are active at doses of less than 1:1000 of the doses used with conventional therapeutic antibodies. Blinatumomab (MT103), a bispecic antibody construct targeting the CD3 molecule of T cells and the CD19 molecule, which has a broad and uniform expression in B cells of dierent stages of dierentiation and all B-cell lymphomas, had high response rates in patients with a refractory response to rituximab.30 If the toxic eects, particularly to the CNS (confusion, disorientation, speech disorder) of this construct can be controlled by modied schedules or subcutaneous application, this new principle could be a substantial improvement in DLBCL immunotherapy. T cells expressing chimeric antigen receptors have an antigen receptor construct (eg, monoclonal antibodyderived single-chain Fv) coupled to signalling molecules (eg, the -chain of the CD3 antigen) that activate T cells that express the respective chimeric antigen receptor. Immunotherapy with genetically modied T cells that express chimeric antigen receptors and target CD19 and CD20 is showing promising results for lymphomas.31
Phase 1/2 1/2 1 1 1 1/2 2 1/2 2 1 1 1 1 NCT trial number* NCT00611208 NCT01032681 NCT00889408 NCT00796731 NCT00720135 NCT01086644, NCT01030536, NCT05159892 NCT00866047 NCT00867087 NCT00337987, NCT00643837 NCT00944905 NCT01015911 Supplementary webreferences .. .. .. .. .. .. 23 .. 24 .. ..

Eligibility T-cell diseases Solid tumours, lymphomas B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma B-cell non-Hodgkin lymphoma Anaplastic large-cell lymphoma B-cell non-Hodgkin lymphoma Peripheral T-cell lymphoma B-cell non-Hodgkin lymphoma, kidney cancer B-cell non-Hodgkin lymphoma, renal cell carcinoma B-cell non-Hodgkin lymphoma, chronic lymphocytic leukaemia Cutaneous T-cell lymphoma, peripheral T-cell lymphoma

NCT00586391, NCT01087294 .. NCT00438802 ..

*NCT trial number: for trial registered with ClinicalTrials.gov, see http://www.ClinicalTrials.gov. See webappendix for these references. Refractory and relapsed.

Table 3: Conjugated antibody and other antibody constructs

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However, the logistics of this approach are complex and will prohibit its widespread use. Table 3 lists other antibody-conjugate constructs.

Other targeted therapies

The growing knowledge of mechanisms of lymphomagenesis and signal-transduction pathways has provided many targets for new drugs. These new drugs under clinical investigation for DLBCL include immunomodulators, inhibitors of histone deacetylases, kinases, mTOR, and drugs targeting apoptosis pathways. Thalidomide and its derivatives represent a class of antineoplastic drugs with anti-inammatory, antiangiogenic, and immunomodulatory properties. They target tumour cells by direct cytotoxicity and indirectly by interfering with several components of the microenvironment. Thalidomide analogues with antitumour activity equal to or greater than the parent compound, but less neurotoxic, include lenalidomide, pomalidomide, and actimid, which are active in multiple myeloma and myelodysplastic syndromes. Based on in-vitro data, it seems that antiproliferative eects and downregulation of cytokines crucial for the survival and growth of haematological malignancies (tumour necrosis factor , interleukin 6, interleukin 8, VEGF) are most important besides inhibition of regulatory T cells, potent costimulatory eects on eector T cells, and activation of natural killer cells. Moreover, immunomodulating drugs inhibit angiogenesis and are directly antiproliferative through the inhibition of the AKT pathway and enhancement of the expression of the p21 tumour suppression gene. However, these in-vitro eects have yet to be corroborated in vivo and much is yet to be elucidated regarding the complex interplay of immunomodulatory cytokines in vivo. Lenalidomide was active in relapsed and refractory DLBCL with response rates of 2030% in phase 2 studies.32,33 The most common side-eects are neutropenia and thrombocytopenia. Lenalidomide (25 mg) for 10 days plus fully-dosed R-CHOP-21 regimen was feasible without treatment delays in a phase 1/2 study of aggressive B-cell lymphomas.34 Results with pomalidomide and actimid in aggressive lymphomas have not yet been reported. Proteasome inhibitors interfere with the ubiquitinproteasome pathway, which is essential for the degradation of intracellular proteins in eukaryotic cells. Since many proteins involved in the regulation of the cell cycle, apoptosis, and in the activation of transcription factors are substrates for proteasome-mediated degradation, interference with the ubiquitin-proteasome pathway is an attractive strategy in cancer therapy. Thrombocytopenia and peripheral neuropathy are the most relevant toxic eects of bortezomib, the rst proteasome inhibitor. Mantle-cell lymphomas were the lymphomas most sensitive to bortezomib, which lead to its approval for relapses of this lymphoma entity. The activity of bortezomib monotherapy for DLBCL was disappointing. However, since IB, an inhibitor of nuclear factor B (NFB), is a
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substrate of the 26S proteasome, stabilisation of IB by the reduction of its degradation via proteasome inhibition should result in decreased NFB activity. This stabilisation makes proteasome inhibition attractive in the treatment of neoplasms with a high expression of target genes of the NFB family of transcription factors, such as the activated B-cell type of DLBCL.19 In a small study with 27 patients with DLBCL,35 bortezomib combined with chemotherapy resulted in a better response rate (83% vs 13%; p<0001) and median overall survival (108 months vs 34 months; p=0003) in activated B-cell compared with germinal centre DLBCL, which suggest that bortezomib enhances the activity of chemotherapy in activated B-cell DLBCL, but not in germinal centre DLBCL, and provides an approach to genetically distinct DLBCL subtypes. If conrmed, the combination of a CHOP-like chemotherapy with bortezomib would represent the rst dierential therapy for the two major biological subtypes of DLBCL. Clinical results are not yet available for other strategies to downregulate NFBeg, by inhibitors of I kinase and janus kinase signalling. Several new proteasome inhibitors are now in clinical trials for lymphomas, including peptide boronic acid analogues MLN9708 (NCT00893464), CEP-18770 (NCT00572637), carlzomib (an epoxyketone related to epoxomycin, a natural product isolated from Actinomyces spp), PR-047, and NPI-0052, a small -lactone compound derived from fermentation of Salinispora spp, a gram-positive actinomycete. These molecules are inhibitors of proteasome in vitro, but show dierences in enzyme binding kinetics, which might result in dierent ecacy and safety proles. Although comparisons of ecacy with bortezomib are not available, in-vitro results of these drugs in cell lines are encouraging.36 The mTOR (mammalian target of rapamycin) kinase is an essential mediator of growth signals that originate from phosphatidylinositol 3 kinase (PI3K). mTOR is upregulated by AKT after activation of PI3K and suppressed via the AMP-activated protein kinase system. Downstream targets of mTOR, p70 S6 kinase, and 4E binding protein are important regulators of protein synthesis, and by raising cyclin-D1 are also drivers of the cell cycle. Inhibition of mTOR by rapamycin (also called sirolimus), originally developed as an immunosuppressive drug, interferes with oncogenic transformation and tumour development by gain-of-function in PI3K signalling. The discovery that mTOR is involved in several pathways that are activated in various neoplasms led to clinical trials with mTOR inhibitors. Temsirolimus and everolimus are licensed for the treatment of renal cancer. In DLBCL, everolimus induced responses in seven (35%) of 20 patients with relapsed or refractory DLBCL.37 Temsirolimus showed activity in a randomised study versus the investigators choice of salvage therapy in relapsed and refractory mantle-cell lymphoma38 that led to its approval for relapsed mantle-cell lymphoma in 2010. The most common side-eects are thrombocytopenia,
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anaemia, and neutropenia. Non-haematological sideeects include hyperglycaemia, hyperlipidaemia, and asthenia. In DLBCL 10 (45%) of 22 patients39 responded to treatment with temsirolimus, but ecacy data for ridaforolimus in aggressive lymphomas have not yet been reported. Compounds interfering with the mTOR pathway and in trials are sirolimus (NCT00776373), the pan-PI3K inhibitor GDC-0941 (NCT00876122), the dual inhibitor of PI3K and mTOR kinases GDC-0980 (NCT00854126), the pan-PI3K/mTOR inhibitor SF1126 (NCT00907205), XL765 a selective dual inhibitor of class I PI3K isoforms PI3K/TORC1/TORC2 (NCT00485719) and mTOR, and CAL-101 (NCT01088048).40,41 Histone deacetylases (HDACs) are epigenetic regulators which catalyse the removal of acetyl moieties from histones and non-histone proteins, including transcription factors and chaperones. HDACs can regulate expression of tumour suppressor genes and activities of transcriptional factors involved in cancer initiation and progression. Aberrant histone deacetylation, due to increased HDAC activity and expression, often relate to pathological gene repression and neoplastic transformation. Several groups of HDAC inhibitors have been developed: hydroxamates, cyclic peptides, aliphatic acids, and benzamides. Vorinostat, a pan-HDAC inhibitor, has been approved by the FDA for relapsed or refractory cutaneous T-cell lymphoma.42 Although vorinostat has additive and synergistic eects with other drugs, its role in the treatment of DLBCL and mantle-cell lymphoma has not been dened. Side-eects include diarrhoea, nausea, fatigue, alopecia, thrombocytopenia, and neutropenia. Belinostat, a hydroxamate HDAC, has shown activity in DLBCL in a phase 1 study.43 Romidepsin (depsipetide),44 a selective inhibitor of class 1 and 2 HDACs approved by the FDA for relapsed cutaneous T-cell lymphomas, in combination with belinostat
Specication CS055/HBI-8000 Belinostat Entinostat Panabinostat PCI-24781 Romidepsin Valproic acid Vorinostat Benzamide type inhibitor of HDAC 1,2,3,10 Hydroxamic acid HDAC inhibitor HDAC inhibitor Cinnamic hydroxamic acid analogue HDAC inhibitor Broad spectrum HDAC inhibitor Depsipeptide HDAC inhibitor Synthetic derivative of propylpentanoic Synthetic hydroxamic acid derivative

synergise the antineoplastic eect of bortezomib in mantle-cell lymphoma cell lines.45 Table 4 lists other HDAC inhibitors in clinical trials. The intrinsic cell-death pathway, also known as the mitochondrial apoptotic pathway, is triggered at the mitochondria by a wide range of signals. The most important regulators belong to the B-cell lymphoma 2 (Bcl-2) family. The antiapoptotic family members Bcl-2, Bcl-B, Bcl-Xl, A1, and Mcl-1 share the Bcl-2 homology (BH) domains 14. Proapoptotic eects are mediated by the multidomain family members Bax and Bak and the BH3only proteins, Bad, Bik, Bid, Bim, Bmf, HrK, Noxa, and Puma. Upon activation, Bax and Bak induce the release of cytochrome C into the cytoplasm where it activates the enzyme cascade that leads to apoptosis, whereas the antiapoptotic Bcl-2 family members inhibit the release of cytochrome C by blocking the activation of Bax and Bak. The proapoptotic BH-3-only proteins act upstream of Bax and Bak by binding Bcl-2 proteins and releasing Bax and Bad.46 Bcl-2 is overexpressed in about 40% of DLBCL. The rst construct tested clinically was the Bcl-2 antisense-nucleotide oblimersen, which led to a partial responce in two of seven patients with DLBCL; however, it seems to be more active in indolent lymphomas.47 Among small-molecule Bcl-2 inhibitors, the Bad-like BH3 mimetics induce apoptosis by binding to Bcl-2, Bcl-Xl, and Bcl-W and releasing the proapoptotic members of the Bcl-2 family. ABT-263 and ABT-737 are in clinical trials for lymphomas and small-cell lung cancer.48,49 The major side-eect is dose-dependent acute thrombocytopenia. Survivin is a bifunctional inhibitor of apoptosis proteins that has been implicated in protection from apoptosis and regulation of mitosis. It is expressed in most human neoplasms, but is absent in normal tissues. Spontaneous antisurvivin T-cell reactivity has been noted in patients
Phase NCT trial number* NCT00865969 NCT00020579 NCT01032148, NCT00962507, NCT01090973, NCT00901147, NCT00978432, NCT00967044 NCT00724984 NCT01016990 Supplementary webreferences 25 .. .. 26 27 28 ..

Eligibility

Advanced solid tumours and lymphoma 1/2 Peripheral T-cell lymphoma Lymphomas, solid tumours Hodgkins and non-Hodgkin lymphoma Lymphoma Peripheral T-cell lymphoma 2 1/2 1/2 1/2 2

Hodgkins and non-Hodgkin lymphoma, 2 chronic lymphocytic leukaemia Non-Hodgkin lymphoma 1/2

NCT00992446, NCT00837174, NCT00810576, .. NCT00972842, NCT00764517, NCT00601718, NCT00787527, NCT00691210, NCT00882206, NCT00703664, NCT00972478 29 30

MGCD0103 SB939

2-aminobenzamide inhibitor of HDAC 1, 2, 3 Small molecule HDAC-1/2 inhibitor

Diuse large B-cell lymphoma Advanced malignancies

1/2 1

HDAC=histone deacetylase. *NCT trial number: for trial registered with ClinicalTrials.gov, see http://www.ClinicalTrials.gov. See webappendix for these references. Refractory and relapsed.

Table 4: Histone deacetylase inhibitors in trials for lymphomas

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with cancer, which makes survivin an attractive target for anticancer immunotherapy.50 YM155, a survivin suppressant that improves the antitumour eects of rituximab in DLBCL, achieved responses lasting from 8 months to longer than 48 months in a phase 1/2 study of patients with non-Hodgkin lymphoma.51 Side-eects were stomatitis, pyrexia, nausea, and reversible elevations in serum creatinine. Table 5 lists other new drugs interfering with the apoptosis pathway. Heat shock proteins are chaperones needed for the stability and function of proteins implicated in cell growth, dierentiation, and survival. Inhibition of these proteins results in increased degradation of so-called client proteins such as kinases, signal transducer proteins, and mutated oncogenic proteins. The rst inhibitors of heat shock proteins are in early clinical trials (table 5). Tyrosine kinase inhibitors block tyrosine kinases, which are part of the signalling process within cells. These inhibitors can block one signal or more than one signal (multi-tyrosine kinase inhibitors). Protein kinase C (PKC), a pivotal enzyme in B-cell signalling and survival, is overexpressed in many lymphoma subtypes. Enzastaurin, an oral serine threonine kinase inhibitor, suppresses signalling through PKC, PI3K, and AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumour-induced angiogenesis in vitro. Moreover, PKC expression was recently reported as a guide to prognosis in DLBCL.52 Enzastaurin is active in relapsed mantle-cell lymphoma and DLBCL.53,54 Side-eects recorded were fatigue,
Specication AT-101 Oblimersen Obatoclax ABT-263 Aplidin (plitidespin) LY2181308 YM155 AEG35156 Mapatumumab Lexatumumab Conatumumab Apo2L/TRAIL Tanespimycin SNX-5422 Endostatin OPB-31121 NPI2358 R-gossypol acetic acid BH3 mimetic Anti-sense oligonucleotide Small-molecule Bcl-2 antagonist Small molecule Bcl-2 antagonist Cyclic depsipeptide, triggers mitochondrial cytochrome C release Survivin anti-sense oligonucleotide Small-molecule survivin inhibitor Second generation anti-sense oligoncleotide blocks X-linked inhibitor of apoptosis (XIAP) TRAIL receptor-1 agonist antibody TRAIL-R2 (death receptor 5) agonist antibody TRAIL-R2 agonist antibody Recombinant TRAIL activates to DR4 + DR5 Promotes degradation of oncogenic signalling proteins by binding to HSP-90 HSP-90 inhibitor Recombinant fragment of type XVIII collagen induces endothelial cell apoptosis Small molecule STAT3 inhibitor Diketopiperazin derivative, block colchicin-binding site of tubulin, disrupts vasculature Eligibility B-cell malignancies Follicular lymphoma Lymphomas Lymphomas

oedema, headache, motor neuropathy, and thrombocytopenia. Enzastaurin is being assessed in a large international trial for consolidation of higher-risk DLBCL in complete remission after R-CHOP. Syk is a tyrosine kinase involved in signal transduction of the antigen receptors in B cells and T cells. Fostamatinib, an oral Syk inhibitor, was well tolerated with a response rate of 22% including one complete remission in 23 patients with DLBCL.55 Tipifarnib, a farnesyltransferase inhibitor, is active in mantle-cell lymphoma.56 Table 6 lists other tyrosine kinase inhibitors. The aurora kinase family has three members: aurora A, B, and C. The aurora A and B kinases are essential regulators of cell division, which makes them attractive targets for therapeutic inhibition. Table 6 lists aurora kinase inhibitors in clinical evaluation for cancer. The activity of cyclin-dependent kinases (CDKs) is often upregulated in malignant cells. Alvocidib (also called avopiridol), a pan-CDK inhibitor with substantial activity in chronic lymphocytic leukaemia,57 led to partial remission in a phase 1/2 study58 in one of ten patients with relapsed or refractory DLBCL. Major side-eects were neutropenia, vomiting, and diarrhoea. Table 6 lists other CDK inhibitors being assessed for the treatment of lymphomas.

Aggressive T-cell non-Hodgkin lymphomas

The WHO classication1 distinguishes 12 subtypes of T-NHL. Peripheral T-cell lymphomas not otherwise specied (PTCL-NOS), systemic anaplastic large-cell
Phase 2 2 2 1 2 1 1 1/2 1 1 1/2 1/2 1/2 1 2 1 1 NCT trial number* NCT00275431 NCT00301795 NCT00538187 NCT00406809 NCT00884286 NCT01007292 NCT00633594 NCT00428272 NCT00400764 NCT00644072 NCT00974324 NCT00511082 NCT00322608 Supplementary webreferences 31 .. 32 33 34 35 36 .. 37 .. 38 39, 40 41 .. .. .. ..

Aggressive lymphomas Advanced malignancies Non-Hodgkin lymphoma Mantle-cell lymphoma Advanced malignancies Solid tumours, lymphoma Lymphomas Lymphomas Lymphomas Lymphoma, solid tumours Peripheral T-cell lymphoma Non-Hodgkin lymphoma, multiple myeloma Advanced lymphoma and solid tumours

*NCT trial number: for trial registered with ClinicalTrials.gov, see http://www.ClinicalTrials.gov. See webappendix for these references. Refractory and relapsed.

Table 5: Molecules interfering with the apoptosis pathway

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Specication Imatinib Dasatinib Sorafenib Pazopanib AT9283 Hydroxystauroposporine XL 184 Fostamatinib PCI-32765 BCR-ABL and other kinases SRC family of tyrosine kinases Multi-kinase inhibitor Multi-target tyrosine kinase inhibitor Multi-targeted kinase inhibitor Multi-phosphokinase inhibitor RET, VEGFR2, MET kinase inhibitor Syk kinase inhibitor Bruton's tyrosine kinase-inhibitor

Eligibility T-cell non-Hodgkin lymphoma Solid tumours, lymphomas Diuse large B-cell lymphoma Solid tumours, lymphomas Solid tumours, lymphomas Lymphomas Lymphoma Lymphoma Diuse large B-cell lymphoma, T-cell lymphoma B-cell non-Hodgkin lymphoma, chronic lymphocytic leukaemia Aggressive lymphoma B-cell non-Hodgkin lymphoma Solid tumours, lymphomas Solid tumours, lymphomas Mantle-cell lymphoma, multiple myeloma, chronic lymphocytic leukaemia Lymphomas Haematological malignancies Non-Hodgkin lymphoma, advanced malignancies Non-Hodgkin lymphoma, advanced solid tumours Mantle-cell lymphoma Mantle-cell lymphoma Lymphoma, multiple myeloma Solid tumours, non-Hodgkin lymphoma Solid tumours, lymphomas Mantle-cell lymphoma, diuse large B-cell lymphoma Lymphoma Non-Hodgkin lymphoma, kidney cancer Solid tumours, lymphoma, glioblastoma Solid tumours, lymphoma Solid tumours, lymphoma Solid tumours, lymphoma Lymphoma Mantle-cell lymphoma Advanced solid tumours, lymphoma Solid tumours, lymphoma

Phase 2 1/2 2 1/2 1 1/2 2 1/2 2 2 1 2 1/2 1/2 1/2 1 1/2 1 1 1 2 1 2 1 1 1/2 1 1 1 1 1/2 1/2 1 1/2 1 1/2

NCT trial number* NCT00684411 NCT00608461 NCT00918463 NCT00474929 NCT00674 024 NCT00085319 .. NCT00798096

Supplementary webreferences .. .. 42 .. 43 .. 44 ..

NCT01109069, NCT00849654 .. .. .. 45 NCT00724984 NCT00939770, NCT00585195 NCT00861510 NCT00697346 NCT00652158 NCT00443976 NCT00843050 NCT1011118 NCT00112723 NCT00390117 NCT00779584 NCT00741871 NCT00848601 NCT00458731 NCT00734890 NCT00293345 46 .. 47 .. 48 .. .. .. .. 49 .. .. .. .. 50 .. .. .. 51 52 53 .. ..

PCI-24781 PF-02341066 ARQ 197 ON01910 BI 2536 MLN8237 MLN8054 AT92383 P276-00 PD-0332991 Flavopiridol AT7519M SCH900776 Enzastaurin53,54 SB1518 SGI-1776 Cediranib Vandetanib Telatinib BAY 73-4506 Linifanib Tipifarnib56 Triapine ABT-888

Bruton's tyrosine kinase inhibitor c-MET/hepatocyte growth factor receptor tyrosine kinase inhibitor c-MET/hepatocyte growth factor receptor tyrosine kinase inhibitor Polo-like kinase-1 inhibitor Polo-like kinase-1 inhibitor Aurora kinase inhibitor Selective aurora kinase inhibitor Aurora kinase inhibitor CDKs inhibiting avone CDK4/cyclin D1 kinase inhibitor CDK inhibitor Selective CDKI inhibitor Check-point kinase 1 inhibitor Protein kinase C inhibitor, antiangiogenic JAK-2 inhibitor PIM kinase inhibitor VEGF-R tyrosine kinase inhibitor Tyrosine kinase inhibitor, antiangiogenetic VEGF receptor kinase inhibitor Inhibitor of oncogenic and angiogenic kinases VEGF and PDGF receptor families Farnesyl-transferase inhibitor Ribonucleotide reductase inhibitor Poly(ADP-ribose)-polymerase (PARP) inhibitor

NCT00553189, NCT0740805, 54, 55 NCT00810966, NCT00576654

*NCT trial number: for trial registered with ClinicalTrials.gov, see http://www.ClinicalTrials.gov. See webappendix for these references. Refractory and relapsed.

Table 6: Enzyme inhibitors under clinical investigation for lymphomas

lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL) are the most common forms of PTCL, whereas nasal-type extranodal natural killer/T-cell lymphoma (nNK/T) is more common in east Asia. Most T-cell lymphomas are aggressive, including PTCL-NOS, AILT, and anaplastic lymphoma kinase (ALK)-negative ALCL. ALK-positive ALCL and the cutaneous T-cell lymphomas (cutaneous CD30 anaplastic lymphoma, mycosis fungoides, and Sezary syndrome) have a more
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indolent course and are therefore not discussed in our review. Aggressive T-cell lymphomas have a worse prognosis than aggressive B-cell NHL, with a 5-year disease-free survival of less than 30% in large series. The cornerstone of treating PTCL continues to be CHOP-based chemotherapy, even though in patients being treated the rates of progressions and relapses are substantially more common than in DLBCL.59 Patients with PTCL did
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substantially better when treated with CHOEP (CHOP plus etoposide 100 mg/m days 13) instead of CHOP where 2 weeks and 3 weeks CHOP and CHOEP were compared in a subgroup analysis of PTCL treated in the NHL-B1 and NHL-B2 trials of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL).60,61 These ndings suggested that CHOEP was the preferable chemotherapy regimen for PTCL, at least in younger patients who tolerate CHOEP as well as CHOP.62

Cytotoxic drugs
Pralatrexate is a folate analogue with high anity to the reduced folate carrier (RFC-1), the principal transporter by which natural folates (and antifolates) enter the cell. Classic folate analogues are internalised by RFC-1 in fetal and tumour cells, but not normal tissues. In the PROPEL phase 2 study of pralatrexate in relapsed or refractory, extensively pretreated PTCL, the response rate was 28%, with a complete responce rate of 9% and a median duration of response of 94 months,63 these ndings led to its approval for relapsed PTCL by the FDA. Common side-eects were thrombocytopenia and mucositis, which can be ameliorated with folic acid and vitamin B12. Gemcitabine, a pyrimidine analogue, is licensed for the treatment of advanced pancreatic cancer, is active in DLBCL, cutaneous T-cell lymphomas, and relapsed PTCLwhere a complete response rate of 30% was recorded.64 Side-eects were myelosuppression and transient hepatotoxicity. Various combinations of gemcitabine with other cytotoxic drugs are being assessed (table 1). Purine analogues compete with natural purine nucleosides and inhibit DNA synthesis and repair. Of the older drugs (pentostatin, udarabine, cladribine) pentostatin is active as monotherapy in PTCL.65 The newer purine analogues, nelarabine and forodesine, should be more T-cell selective because of their interactions with purine nucleoside phosphorylase. Forodesine is not incorporated into DNA. As a consequence of the purine nucleoside phosphorylase inhibition, forodesine alters the nucleoside pathway that results in intracellular accumulation of deoxyguanosine triphosphate (dGTP) and lymphocyte death. Forodesine is well tolerated, with fatigue nausea, peripheral oedema, and headache being the most common side-eects.66 Forodesine has substantial activity in CTCL, but results with PTCL have not been reported. Nelarabine, a nucleoside analogue approved for relapsed T-lymphoblastic leukaemia, has only disappointing activity in PCTL.67

Alemtuzumab is a humanised anti-CD52 antibody. CD52 is expressed on all B and T lymphocytes, monocytes, macrophages, eosinophils, natural killer cells, and dendritic cells. Alemtuzumab is approved for the treatment of relapsed and refractory B-chronic lymphocytic leukaemia. However, the expression of CD52 is variable in PTCL, and studies of alemtuzumab in PTCL have included only small numbers of patients. In PTCL, alemtuzumab has been active alone70,71 and in combination with CHOP;72 udarabin, doxorubin, and cyclosphosphamide;73 and dexamethasone, cisplatin and cytarabine.74 Important sideeects of alemtuzumab are infections, in particular cytomegalovirus and Epstein-Barr virus reactivations and Pneumocystis jirovecii pneumonitis. Of major concern are observations of Epstein-Barr virus-induced B-cell lymphoproliferative disorders. These disorders have also been associated with siplizumab, a monoclonal antibody active against CD2, which is expressed on all mature T cells and most natural killer cells.75 Siplizumab was tested in only 29 patients with PTCL. Finally, KW-0761, a humanised antibody to C-C chemokine receptor type 4 (CCR4), expressed in adult T-cell leukaemia and lymphoma and PTCL is active in T-cell disease.12 Denileukin diftitox is a fusion protein (containing interleukin 2 and the diphtheria toxin A chain) approved for CTCL. Adverse eects include fever, chills, nausea, vomiting, myalgias, and arthralgias and transient elevations of hepatic aminotransferases. In a phase 2 study,28 13 of 27 patients with relapsed or refractory PTCL had objective responses, including six complete responses. The combination of denileukin diftitox with CHOP as initial therapy for 15 patients with PTCL achieved eight complete response or complete response uncertain.29

Other targeted therapies

Aberrant signalling pathways in PTCL involving the P13K/AKT/mTOR, the Notch, the Janus/signal transducer and activator of transcription (STAT) pathways, the NFB, the calcineurin/NF of activated T cells pathway, and the mitogen-activated protein kinase (MAPK) cascade provide a plethora of targets for drugs now in development for the treatment of PTCL.76 Of the histone deacetylase inhibitors, vorinostat and romidepsin are approved by the FDA for CTCL. In a phase 2 trial of romidepsin in PTCL,44 ve of 19 patients with relapsed or refractory PTCL responded including two complete responses. Studies with these and other HDAC inhibitors are ongoing, as are studies with immunomodulators and inhibitors of proteasomes and kinases (tables 35).

Antibodies
The anti-CD4 monoclonal antibody zanolimumab was active in a small trial of patients with PTCL.68 The CD30 molecule, initially identied in Reed-Sternberg cells, is overexpressed in ALCLs. Several anti-CD30 antibodies are being assessed in refractory ALCLs and Hodgkins lymphomas.69
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Besides classic cytotoxic drugs, many new compounds have been developed that target a molecule or a pathway relevant for growth or proliferation of lymphomas. Although the specicity of small molecules to their targets
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Search strategy and selection criteria Pubmed was checked for articles in English with the keywords lymphoma therapy and new drugs from 2005 to June 30, 2010, as were the abstract books of the annual meetings of ASH from 2007 to 2009, of ASCO 2010, and of the International Conference on Lymphoma in Lugano of 2005 and 2008. Current lymphoma trials registered at the NCI were also considered for this review. Selection criteria were innovative aspects, the possible impact of new drugs on current treatment strategies, and the quality of the respective clinical trials.

is excellent, it must be kept in mind that specic targeting not only inhibits the function of the targeted molecule, but also has multiple distant eects via a complex regulatory network, the elucidation of which remains a formidable goal for our understanding of the physiology of normal and malignant cells. Besides this fundamental challenge, there are other issues that must be addressed in clinical oncology research. The number of new drugs ready for clinical testing is enormous: for many single targets such as the tyrosine kinases and histone deacytelases many new drugs are available from dierent companies that often dier only slightly with respect to their specicity, clinical activity, and side-eects. The parallel testing of many drugs with identical molecular targets in similar patient populations splits the number of qualifying patients for such trials, resulting in substantial delay in the clinical development of a new compound and in an increase of the costs of early clinical trials. Finally, many of the new molecules have a broad therapeutic window and are rather cytostatic than cytotoxic. As a consequence cytostatic drugs are not necessarily inecacious if no responses are noted in phase 1 and phase 2 trials; rather, their benet might only be detectable when combined with established regimens. Thus, the denition of the maximum tolerated dose cannot be the prime goal of early clinical trials with such drugs; rather it is the denition of a dose that exploits the maximum potential of a new molecule when added to or substituting for another drug of an established combination. That many new drugs might interact with each other when combined in a treatment regimen is another tremendous challenge, which can only be mastered by establishing reliable preclinical models in vitro and in vivo. There is a need to adapt the design of clinical trials away from the classic phase 1/2/3 studies to a design that allows for the fast, but reliable denition of the clinical value of a new drug, thus saving patients and costs on its road to approval.
Contributors MP designed the concept of the manuscript. MP and NM searched published work and selected the references. MP and NM wrote the paper. Conicts of interest MP has received honoraria from Roche, Amgen and GSK; consultancies from Roche, Pzer, and GSK, and has received research support by Roche and Amgen. NM declared no conicts of interest.

References 1 Swerdlow SH, Campo E, Harris NL, et al. WHO classication of tumours of haematopoietic and lymphoid tissues, 4th edn. Geneva: World Health Organization, 2008. 2 Engert A, Herbrecht R, Santoro A, Zinzani PL, Gorbatchevsky I. EXTEND PIX301: a phase III randomized trial of pixantrone versus other chemotherapeutic agents as third-line monotherapy in patients with relapsed, aggressive non-Hodgkins lymphoma. Clin Lymphoma Myeloma 2006; 7: 15254. 3 El Gnaoui T, Dupuis J, Belhadj K, et al. Rituximab, gemcitabine and oxaliplatin: an eective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol 2007; 18: 136368. 4 Corazzelli G, Capobianco G, Arcamone M, et al. Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother Pharmacol 2009; 64: 90716. 5 Coier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diuse large-B-cell lymphoma. N Engl J Med 2002; 346: 23542. 6 Pfreundschuh M, Truemper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab compared with CHOP-like chemotherapy alone in young patients with good-prognosis diuse large B-cell lymphoma: a randomized controlled trial by the Mabthera International Trial (MInT) Group. Lancet Oncol 2006; 7: 37991. 7 Morschhauser F, Marlton P, Vitolo U, et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol 2010; 21: 187076. 8 Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkins lymphoma: phase I/II results. J Clin Oncol 2009; 27: 334653. 9 Mossner E, Brunker P, Moser S, et al. Increasing the ecacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune eector cellmediated B-cell cytotoxicity. Blood 2010; 115: 4393402. 10 Leonard JP, Martin P, Barrientos J, Elstrom R. Targeted treatment and new agents in diuse large B-cell lymphoma. Semin Hematol 2008; 45: S1116. 11 Rosevear HM, Lightfoot AJ, Grith TS. Conatumumab, a fully human mAb against death receptor 5 for the treatment of cancer. Curr Opin Investig Drugs 2010; 11: 68898. 12 Yamamoto K, Utsunomiya A, Tobinai K, et al. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol 2010; 28: 159198. 13 Hagenbeek A, Gadeberg O, Johnson P, et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 2008; 111: 548695. 14 Coier B, Lepretre S, Pedersen LM, et al. Safety and ecacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood 2008; 111: 1094100. 15 Leonard JP, Coleman M, Ketas J, et al. Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkins lymphoma. J Clin Oncol 2005; 23: 504451. 16 Oazoglu E, Stone IJ, Brown L, et al. Macrophages and Fc-receptor interactions contribute to the antitumour activities of the anti-CD40 antibody SGN-40. Br J Cancer 2009; 100: 11317. 17 Advani R, Forero-Torres A, Furman RR, et al. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkins lymphoma. J Clin Oncol 2009; 27: 437177. 18 Trarbach T, Moehler M, Heinemann V, et al. Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 2010; 102: 50612. 19 Wakelee HA, Patnaik A, Sikic BI, et al. Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors. Ann Oncol 2010; 21: 37681. 20 Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 2008; 359: 231323.

www.thelancet.com/oncology Vol 11 November 2010

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Review

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23

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25

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33

34

35

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Hodi FS, ODay SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 71123. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 2009; 15: 644653. Zinzani PL, Tani M, Fanti S, et al. A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diuse large B-cell lymphoma patients. Ann Oncol 2008; 19: 76973. Hamlin PA, Moskowitz CH, Wegner B, et al. Sequential R-CHOP and yttrium-90 ibritumomab tiuxetan (RIT) is a highly eective regimen for high risk elderly patients with untreated DLBCL. 10th International Conference on Malignant Lymphoma; Lugano, Switzerland; June 47, 2008. Abstract 054. Gisselbrecht C, Vose J, Nademanee A, Gianni AM, Nagler A. Radioimmunotherapy for stem cell transplantation in nonHodgkins lymphoma: in pursuit of a complete response. Oncologist 2009; 14 (suppl 2): 4151. Linden O, Hindorf C, Cavallin-Stahl E, et al. Dose-fractionated radioimmunotherapy in non-Hodgkins lymphoma using DOTA-conjugated, 90Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab. Clin Cancer Res 2005; 11: 521522. Fayad L, Patel H, Verhoef G, et al. Safety and clinical activity of the anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) in combination with rituximab in follicular lymphoma or diuse large B-cell lymphoma: preliminary report of a phase 1/2 study. 50th ASH Annual Meeting and Exposition; San Francisco, CA, USA; Dec 69, 2008. Abstract 266. Dang NH, Pro B, Hagemeister FB, et al. Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Br J Haematol 2007; 136: 43947. Foss F, Sjak-Shie N, Goy A, et al. Denileukin diftitox (ONTAK) plus CHOP chemotherapy in patients with peripheral T-cell lymphomas (PTCL), the CONCEPT trial. 49th ASH Annual Meeting and Exposition; Atlanta, GA, USA; Dec 811, 2007. Abstract 3449. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008; 321: 97477. Jensen MC, Poppplewell L, DiGiusto D, et al. A rst-in-human clinical trial of adoptive therapy using CD19-specic chimeric antigen receptor re-directed T-cells for recurrent/refractory follicular lymphoma. 49th ASH Annual Meeting and Exposition; Atlanta, GA, USA; Dec 811, 2007. Abstract 288. Czuczman MS, Vose JM, Zinzani P-L, et al. Conrmation of the ecacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory diuse large B-cell lymphoma: results of an international study. 50th ASH Annual Meeting and Exposition; San Francisco, CA, USA; Dec 69, 2008. Abstract 268. Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkins lymphoma. J Clin Oncol 2008; 26: 495257. Nowakowski G, LaPlant B, Habermann T, et al. A phase I/II trial of lenalidomide and RCHOP (R2CHOP) in patients with newly diagnosed diuse large B-cell (DLBCL) and follicular grade 3 lymphoma. 51st ASH Annual Meeting and Exposition; New Orleans, LA, USA; Dec 58, 2009. Abstract 1669. Dunleavy K, Pittaluga S, Czuczman MS, et al. Dierential ecacy of bortezomib plus chemotherapy within molecular subtypes of diuse large B-cell lymphoma. Blood 2009; 113: 606976. OConnor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carlzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 2009; 15: 708591. Reeder CB, Gornet MK, Habermann TM, et al. A phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed aggressive non-Hodgkin lymphoma. 49th ASH Annual Meeting and Exposition; Atlanta, GA, USA; Dec 811, 2007. Abstract 121. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigators choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 2009; 27: 382229.

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43

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45

46

47

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51

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Smith SM, Pro B, Cisneros A, et al. Activity of single agent temsirolimus (CCI-779) in non-mantle cell non-Hodkin lymphoma subtypes 2008 ASCO Annual Meeting; Chicago, IL, USA; May 30Jun 3, 2008. Abstract 8514. Mita MM, Britten CD, Poplin E, et al. Deforolimus trial 106a phase I trial evaluating 7 regimens of oral deforolimus (AP23573, MK-8669). ASCO Annual Meeting; Chicago, IL, USA; May 30Jun 3, 2008. Abstract 3509. Papadopoulos KP, Markman B, Tabernero J, et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL765, administered orally to patients (pts) with advanced solid tumors. ASCO Annual Meeting; Chicago, IL, USA; May 30Jun 3, 2008. Abstract 3510. Ma X, Ezzeldin HH, Diasio RB. Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs 2009; 69: 191134. Gimsing P, Hansen M, Knudsen LM, et al. A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia. Eur J Haematol 2008; 81: 17076. Piekarz RL, Frye R, Turner M, et al. Responses and molecular markers in patients with peripheral T-cell lymphoma treated on a phase II trial of depsipeptide, FK228. 2005 ASCO Annual Meeting; Orlando, FL, USA; May 1317, 2005. Abstract 3061. Paoluzzi L, Scotto L, Marchi E, et al. Romidepsin and belinostat synergize the antineoplastic eect of bortezomib in mantle cell lymphoma. Clin Cancer Res 2010; 16: 55465. Vogler M, Dinsdale D, Dyer MJ, Cohen GM. Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Dier 2009; 16: 36067. Pro B, Leber B, Smith M, et al. Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma. Br J Haematol 2008; 143: 35560. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 67781. Wilson W, OConnor O, Roberts AW, et al. ABT-263 activity and safety in patients with relapsed or refactory lymphoid malignancies in particular chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). 2009 ASCO Annual Meeting; Orlando, FL, USA; May 29June 2, 2009. Abstract 8574. Andersen MH, Svane IM, Becker JC, Straten PT. The universal character of the tumor-associated antigen survivin. Clin Cancer Res 2007; 13: 599194. Tolcher AW, Mita A, Lewis LD, et al. Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J Clin Oncol 2008; 26: 5198203. Riihijarvi S, Koivula S, Nyman H, et al. Prognostic impact of protein kinase C beta II expression in R-CHOP-treated diuse large B-cell lymphoma patients. Mod Pathol 2010; 23: 68693. Morschhauser F, Seymour JF, Kluin-Nelemans HC, et al. A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann Oncol 2008; 19: 24753. Robertson MJ, Kahl BS, Vose JM, et al. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diuse large B-cell lymphoma. J Clin Oncol 2007; 25: 174146. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has signicant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115: 257885. Rolland D, Ribrag V, Haioun C, et al. Phase II trial and prediction of response of single agent tipifarnib in patients with relapsed/ refractory mantle cell lymphoma: a Groupe dEtude des Lymphomes de lAdulte trial. Cancer Chemother Pharmacol 2010; 65: 78190. Lin TS, Ruppert AS, Johnson AJ, et al. Phase II study of avopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 2009; 27: 601218.

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Tay G, Shapiro G, Disinski M, et al. Phase I/II study of a hybrid schedule of avopiridol in relapsed/refractory mantle cell lymphoma (MCL) and diuse large B-cell lymphoma (DLBCL). 2009 ASCO Annual Meeting; Orlando, FL, USA; May 29June 2, 2009. Abstract 8563. Gisselbrecht C, Gaulard P, Lepage E, et al. Prognostic signicance of T-cell phenotype in aggressive non-Hodgkins lymphomas. Blood 1998; 92: 7682. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 2004; 104: 62633. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 63441. Schmitz N, Nickelson M, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL). Blood 2010; published online July 21. DOI:10.1182/blood-2010-02-270785. OConnor OA. Novel agents in development for peripheral T-cell lymphoma. Semin Hematol 2010; 47 (suppl 1): S1114. Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome. Ann Oncol 2010; 21: 86063. Tsimberidou AM, Giles F, Duvic M, Fayad L, Kurzrock R. Phase II study of pentostatin in advanced T-cell lymphoid malignancies: update of an MD Anderson Cancer Center series. Cancer 2004; 100: 34249. Cheson BD. Clinical management of T-cell malignancies: current perspectives, key issues, and emerging therapies. Semin Oncol 2007; 34: S37. Czuczman MS, Porcu P, Johnson J, et al. Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma: CALGB 59901. Leuk Lymphoma 2007; 48: 97103.

68

69 70

71

72

73

74

75

76

DAmore F, Relander T, Hagberg H, et al. HuMax-CD4 (zanolimumab), a fully humanized human monoclonal antibody: early results of an ongoing clinical trial in CD4+ peripheral T-cell lymphomas of non-cutaneous type. 47th ASH Annual Meeting and Exposition; Atlanta, GA, USA; Dec 1013, 2005. Abstract 3354. Castillo J, Winer E, Quesenberry P. Newer monoclonal antibodies for hematological malignancies. Exp Hematol 2008; 36: 75568. Enblad G, Hagberg H, Erlanson M, et al. A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood 2004; 103: 292024. Zinzani PL, Alinari L, Tani M, et al. Preliminary observations of a phase II study of reduced-dose alemtuzumab treatment in patients with pretreated T-cell lymphoma. Haematologica 2005; 90: 70203. Gallamini A, Zaja F, Patti C, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as rst-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 2007; 110: 231623. Weidmann E, Hess G, Chow KU, et al. A phase II study of alemtuzumab, udarabine, cyclophosphamide, and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas. Leuk Lymphoma 2010; 51: 44755. Kim SJ, Kim K, Kim BS, et al. Alemtuzumab and DHAP (A-DHAP) is eective for relapsed peripheral T-cell lymphoma, unspecied: interim results of a phase II prospective study. Ann Oncol 2009; 20: 39092. OMahony D, Morris JC, Stetler-Stevenson M, et al. EBV-related lymphoproliferative disease complicating therapy with the anti-CD2 monoclonal antibody, siplizumab, in patients with T-cell malignancies. Clin Cancer Res 2009; 15: 251422. Zhao WL. Targeted therapy in T-cell malignancies: dysregulation of the cellular signalling pathways. Leukemia 2010; 24: 1321.

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