HODGKIN LYMPHOMA: NEW AND OLD

Novel therapy for Hodgkin lymphoma Connie Lee Batlevi1 and Anas Younes1 1Lymphoma

Service, Memorial Sloan-Kettering Cancer Center, New York, NY

The treatment of Hodgkin lymphoma (HL) relies on multimodality treatment with standard chemotherapy, radiation therapy, and autologous or allogeneic stem cell transplantation in cases of relapsed disease. Genomic advances in HL provided insights into deregulation of key nodal signaling pathways, including the PI3K, NF-␬B, and JAK/STAT pathways, which are amenable to small-molecule targeting. Understanding how HL cells interact and depend on their microenvironment for survival signals and immune protection may uncover other such pathways. Small-molecule targeting has the potential to dramatically improve treatment outcomes, especially in patients with highly refractory disease and those with poor tolerance to existing chemotherapies. As novel therapies continue to be developed for HL, the challenge will be to address the needs of high-risk groups, reduce long-term therapy-related morbidity, position current established treatments with novel therapies, and concurrently develop biomarkers to aid in patient selection. Brentuximab vedotin, which was approved in 2011, is already shifting the treatment paradigm of HL. Undoubtedly, other novel therapeutics in the pipeline will affect positively the landscape of treatment in HL.

Introduction Hodgkin lymphoma (HL) is an uncommon malignancy with a bimodal incidence curve and approximately 9000 cases diagnosed annually in the United States. Although HL has remained a largely curable disease, approximately 20% of patients will not be cured with currently available therapy and will require subsequent treatments. Classical HL (cHL) makes up 95% of the cases of HL and is characterized by rare Hodgkin and Reed Sternberg (HRS) cells resting in a reactive infiltrate composed of lymphocytes, histiocytes, eosinophils, and plasma cells, with HRS cells comprising ⬍ 5% of the tumor volume. The remaining cells are benign, reactive, inflammatory cells that contribute to HRS cell growth and survival. Novel therapeutics for HL should capitalize on this unique pathology and on the differential expression of cell surface antigens, oncogenic dependence of HRS cells on activated intracellular signaling pathways, and induction of anti-HRS cell immunity by modulating the microenvironment (Figure 1). In this review, we summarize recent updates on the use of monoclonal antibodies, small-molecule signal transduction inhibitors, epigenetic modulators, and agents that modulate the microenvironment.

Monoclonal antibodies Therapeutic antibodies targeting cell surface receptors have contributed to standard-of-care treatments for multiple solid and hematologic malignancies. In HL, targeting cell surface receptors within the TNF and BCR pathways has demonstrated efficacy.

CD30 CD30 is a member of the TNF cell receptor superfamily that is highly expressed in HRS cells, but with highly restricted expression in normal cells. After several failed attempts to develop naked anti-CD30 antibody therapy, remarkable progress was achieved by conjugating the naked antibody SGN30 to antitubulin monomethyl auristatin E to generate the antibody drug-conjugate brentuximab vedotin. In a pivotal phase 2 clinical trial in patients who were previously treated with autologous stem cell transplantation, brentuximab vedotin showed an overall response rate (ORR) of 75%,

394

with 34% of patients achieving complete remission (CR; Figure 2, Table 2).1 Similarly, brentuximab vedotin resulted in an ORR of 71% and a CR of 34% in 14 transplantation-naïve patients, resulting in a 56% conversion rate to transplantation eligibility after therapy.2 Furthermore, retreatment with brentuximab vedotin elicited a clinically relevant response in both HL and systemic anaplastic large cell lymphoma patients.3 The success of brentuximab vedotin prompts the integration of this fairly well tolerated therapy with existing standard chemotherapy. Initial experience of combining brentuximab vedotin with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) showed significant pulmonary toxicity. When bleomycin was eliminated from this regimen, no pulmonary toxicity was observed, while maintaining a high response rate.1 Based on this data, an international randomized study comparing standard ABVD with AVD (doxorubicin, vinblastine, dacarbazine) plus brentuximab vedotin is currently being conducted. In the secondline setting, a sequential therapy of brentuximab vedotin followed by ICE (ifosfamide, carboplatin, etoposide) chemotherapy is currently being investigated in transplantation-eligible patients with relapsed and refractory HL. Although brentuximab vedotin has significant activity in HL, other strategies to target CD30 have been disappointing. Most recently, a novel tetravalent bispecific antibody against CD30 and CD16 (AFM13), which recruits natural killer cells and macrophages to CD30⫹ regions to illicit an immune response, was evaluated.4 Early results from the phase 1 trial demonstrated reasonable safety but limited clinical efficacy.4

CD20 The rationale for targeting CD20 in patients with classical HL is to target HRS cells, which sometimes express CD20, but also to eliminate CD20-expressing reactive B cells in the microenvironment, which can provide survival signals to HRS cells. Two phase 2 trials of rituximab plus ABVD (R-ABVD) were reported recently. In the first study, R-ABVD therapy resulted in a 5-year event-free survival rate of 83%5; in the second, it resulted in a

American Society of Hematology

Figure 1. Mechanism of action of novel agents in HL.

3-year event-free survival rate of 83%.6 These trials provided rationale to conduct multicenter, randomized clinical trials comparing rituximab-ABVD with standard ABVD in patients with high-risk, advanced-stage cHL. However, with the approval of brentuximab vedotin, it remains unclear where CD20-targeted therapy would fit in the treatment of patients with classical HL.

CD40 and CD80 CD40 and CD80 were recently targeted with HCD122 and galiximab, with modest clinical activity. HCD122 (lucatu-

mumab) is an antagonist monoclonal antibody against the transmembrane CD40 receptor. In a phase 1a clinical trial, lucatumumab administered every 4 weeks showed a 10% partial remission (PR) rate. In a subsequent phase 2 trial, 3 of 18 (17%) patients with relapsed HL achieved PRs.7 Galiximab is a chimeric anti-CD80 antibody that has also demonstrated limited clinical activity, with an ORR of 10.3% and a median PFS of 1.6 months in a panel of 30 patients with heavily pretreated cHL.8 Accordingly, no further development of these agents are being pursued in patients with HL.

Figure 2. Response rate of select therapies in HL.

Hematology 2013

395

Table 1. Selected PI3K inhibitors in clinical trials PI3K inhibitor

Administration

Target

Clinical trial no.

CAL-101 IPI-145 BAY80–6946 TGR-1202 BKM-120 CUDC-907 AMG-319

Oral Oral IV Oral Oral Oral Oral

p110 subunit PI3K␦ PI3K␥ and PI3K␦ Pan-class I PI3K PI3K␦ Pan-PI3K PI3K and HDAC PI3K␦

NCT01393106 NCT01476657 NCT01660451 (NHL) NCT01767766 (CLL, NHL, PTCL) NCT01719250 (NHL) NCT01742988 (lymphoma, MM) NCT01300026

CLL indicates chronic lymphocytic leukemia; NHL, non-HL; PTCL, peripheral T-cell lymphoma; and MM, multiple myeloma.

PD1/PD-L1 HRS cells aberrantly express PD-L1, which is typically expressed on APCs. PDL-1 interacts with the PD-1 receptor on T cells to dampen the immune response by inhibiting TCR signaling.9 Several antibodies targeting PD-1 are currently being evaluated for the treatment of a variety of human cancers and are showing promising clinical activity. CT-011 is a humanized anti-PD-1 monoclonal antibody that was evaluated recently in patients with relapsed B-cell malignancies, but has not been investigated in patients with HL.10,11 Nivolumab (BMS-936558) is a monoclonal anti-PD-1 antibody actively being studied in a phase 1 trial for hematologic malignancies, including patients with relapsed HL. The results of this trial are highly anticipated.

Targeting oncogenic signaling pathways Constitutive activation of the JAK/STAT, NF-␬B, PI3K, and MEK/ERK pathways protect HRS cells from apoptotic signals.12 These same pathways are important in supporting the inflammatory microenvironment that contributes to survival and immune recognition of the tumorigenic HRS cells. As a result, targeting these nodal pathways by small-molecule inhibitors has a dual effect on the HRS cells and the microenvironment (Figure 1).

IPI-145 may have clinical activity in patients with relapsed HL. Other PI3K inhibitors are also being evaluated in this disease (Table 1). To date, no data exist on targeting AKT in patients with HL. However, there are clinical data on targeting the downstream mTOR kinase. In a phase 2 study, the mTOR inhibitor everolimus produced an ORR of 47% in 19 patients (Table 2).14 A confirmatory multicenter phase 2 study that enrolled 57 patients with cHL also resulted in an ORR of 42%. Class-related side effects were observed and included stomatitis, thrombocytopenia, fatigue, and grade 1/2 pneumonitis in 6 patients.15 The results were encouraging enough to prompt additional evaluation of rapalogs in combination with histone deacetylase (HDAC) inhibitors because in vitro data suggested synergy.16,17 An ongoing phase 1/2 study combined everolimus (10 mg orally) and panobinostat (20 mg IV 3 times weekly) in patients with lymphoma. The dose-limiting toxicity was thrombocytopenia. Early results from the phase 1 portion of the study involving 13 patients with HL showed an ORR of 50%, with 71% of the patients having a tumor reduction of ⫺12% to ⫺72%.18 These results compare favorably with the single-agent activity of each drug (Figure 2).

JAK/STAT PI3K/AKT/mTOR PI3K is a ubiquitously expressed phosphokinase that transduces extracellular signals from cell surface receptors such as CD40, chemokine receptors, and BCR (Figure 1). There are 4 isoforms of PI3K: ␣, ␤, ␥, and ␦. Activation of PI3K results in activation of downstream kinases, including AKT and mammalian target of rapamycin (mTOR), which regulate several key cellular functions including survival, metabolism, and immunity. PI3K␦ plays a key role in promoting B-cell survival and therefore is being actively targeted in B-cell malignancies. Idelalisib (GS-1101 or CAL101) is an oral PI3K␦-selective small-molecule inhibitor that demonstrated promising clinical activity in a variety of B-cell malignancies.13 Its activity in patients with relapsed HL is currently being evaluated. In a different strategy, a dual inhibitor of PI3K␦ and PI3K␥ and PI3K␦ was developed to produce the small-molecule inhibitor IPI-145. Early results from an ongoing phase 1 clinical trial demonstrated that

The JAK/STAT signaling pathway is frequently activated in HRS cells. Activation mutations of JAK2 are rare in patients with lymphoma. In HL, the JAK/STAT pathway is activated as a result of genomic amplification of JAK2 and/or inactivating mutations in an inhibitor of JAK activity, SOCS1.12 A proof of principle of the therapeutic potential of JAK inhibitors in HL was shown by a phase 1 study of the JAK inhibitor SB1518, a selective inhibitor of JAK2 and FLT3. In that study, 14 of 34 total lymphoma patients had cHL. Of these 14 patients with cHL, 6 patients had stable disease with treatment.19 In addition to a direct antitumor effect, JAK inhibitors may also induce favorable immunomodulatory effects. AZD1480, a JAK1/2 inhibitor, displayed immunomodulatory effects at low concentrations by down-regulating the expression of Th2 cytokines and chemokines (IL-13 and TARC), as well as STAT3-mediated reduced expression of PD-L1 and PD-L2, which are involved in immune recognition. These results support the theory that JAK

Table 2. Response rates achieved with single agents in patients with relapsed HL Agent Brentuximab Everolimus Vorinostat Mocetinostat Panobinostat Entinostat

396

Target

Administration

N

ORR

CR

Reference

CD30 mTOR Class I/II HDAC HDAC 1, 2, weak HDAC 3, 11 Class I/II/IV HDAC HDAC 1, 3

IV PO PO PO PO PO

102 19 25 51 129 49

75% 47% 4% 27% 27% 16%

34% 5% 0% 4% 4% 0%

Younes et al1 Johnston et al14 Kirschbaum et al29 Younes et al32 Younes et al33 Younes et al35

American Society of Hematology

HDAC inhibitors with activity against class I and II HDACs. In vitro experiments demonstrated that vorinostat has a higher IC50 against HL cell lines compared with other HDAC inhibitors. This weak in vitro activity was also associated with a weak clinical activity, with only one patient achieving PR in a phase 2 trial involving 25 patients with HL (Table 2).29

Mocetinostat

Figure 3. Effects of HDACs on tumor response.

signaling modulates the microenvironment of HL and controls autoimmunity in HL.9,20-22

Mocetinostat (MGCD0103) is an oral nonhydroxamate HDAC inhibitor that selectively inhibits HDAC 1, 2, 3 and 11.30,31 A phase 2 trial of 51 patients with relapsed or refractory HL evaluated dose escalation of mocetinostat with a cohort of 23 patients treated with 110 mg of mocetinostat 3 times a week and a second cohort of 28 patients treated with 85 mg of mocetinostat 3 times a week.32 Toxicities include thrombocytopenia, fatigue, pneumonia, anemia, and pericardial effusion, but the ORR was 27%, which is suggestive of clinical activity (Figure 2, Table 2).32

Panobinostat NF-␬B NF-␬B is activated in HRS cells by multiple genetic alterations. REL, a transcription factor of the NF-␬B family, is amplified in ⬃ 50% of cHL. Mutations and deletions of NF-␬B inhibitors such I␬B␣ have also been observed.12 In other cases, aberrant secretion of cytokines in HL microenvironment can also result in activation of NF-␬B. Based on preclinical data demonstrating that bortezomib can inhibit NF-␬B and induce cell death in HRS-derived cell lines, bortezomib was evaluated in patients with relapsed HL. However, 2 independent small studies reported that bortezomib has no significant clinical activity in patients with relapsed HL.23,24 Preclinical data suggested a synergy between bortezomib and chemotherapy, prompting combination of bortezomib with ICE chemotherapy, which showed encouraging early results: the ORR was 70% and the CR was 33%.25 As brentuximab vedotin is being combined with ICE chemotherapy in transplantation-eligible patients with relapsed HL, it is unlikely that bortezomib plus ICE will advance in the clinical development for this disease.

Epigenetic therapy Epigenetic events such as acetylation, methylation, ubiquitination, and phosphorylation of histones control the accessibility of the chromatin structure for DNA transcription, replication, repair and cellular development. Human HDACs are classified into 4 classes: class I includes HDAC 1, 2, 3, and 8, which are localized to the nucleus with ubiquitous tissue expression; class II includes HDAC 4, 5, 6, 7, 9, 10, which have variable cellular localization; class III includes NAD-dependent homologs of yeast, SIRT 1-7, which are not being targeted by currently available HDAC inhibitors; and class IV is composed of HDAC 11.26 Preclinical and clinical experiments have demonstrated that HDAC inhibitors may have a potential therapeutic value in patients with HL by a direct antitumor effect plus an indirect immunoregulatory effect (Figure 3).16 HDAC inhibitors reduce the secretion of the chemokine TARC (CCL17), which is responsible for T-cell chemotaxis.16,27 HDAC inhibitors may also restore antitumor immunity by up-regulating OX40L and disrupting the interaction between PD-1 and PD-L1/2 interactions, which are required for the generation of memory T cells and self-recognition by regulatory T cells.28 Base on these preclinical data, several HDAC inhibitors have been evaluated recently for the treatment of relapsed HL and have shown encouraging results (Figure 1). Vorinostat is one of the earliest

Hematology 2013

Panobinostat is an oral pan-HDAC inhibitor. A phase 2 clinical trial testing 40 mg panobinostat in 129 patients with relapsed cHL showed an ORR of 27%, with 5 CRs and 30 PRs (Figure 2, Table 2).33 Biological activity was detected by an early decline in serum TARC levels. Based on preclinical data suggesting synergy with mTOR inhibitors, panobinostat in combination with everolimus is being studied currently.16,17

Entinostat Entinostat is a class I isoform-selective HDAC inhibitor shown preclinically to induce apoptosis, block promoting factors, and up-regulate T-cell coactivators.34 These results led to the phase 2 study administering entinostat in 2 dosing schemas: 10-15 mg every other week (n ⫽ 33) or 15 mg weekly for 3 weeks (n ⫽ 16) in 28-day cycles.35 Thirty-eight patients were evaluable for response, resulting in 6 patients with PR (ORR 16%) and 45% with SD (Table 2).35 Progression-free survival was short at 3.8 months.35

Immunomodulators The importance of cellular immunity in regulation of HL suggests that immunomodulatory agents may have activity in this disease. Lenalidomide is an immunomodulatory agent with antiangiogenic properties. A phase 2 multicenter study of lenalidomide given in an oral daily dose of 25 mg on days 1-21 of a 4-week cycle in patients with relapsed or refractory HL demonstrated modest single-agent activity.36 Thirty-eight patients with a median of 4 prior therapies demonstrated an ORR of 19%, 1 patient with CR, 6 patients with PR, and 5 patients with stable disease (Figure 2). The most common dose-limiting toxicities were cytopenias, rash, and hepatic toxicity.

Conclusion The development of new therapies has been stagnant in HL for more than 30 years. Since 1977, brentuximab vedotin is the only new agent to be approved by the Food and Drug Administration for the treatment of HL. Many new small-molecule inhibitors have promising clinical activity, paving the way for a revolution in the treatment of HL (Figure 2). Although some seem to have direct activity as single agents (Table 2), others potentially reverse chemoresistance and may have activity when combined with either other smallmolecule inhibitors or traditional chemotherapy. Future investigations should focus on identifying predictive biomarkers to help select patients who are more likely to respond to these novel agents.

397

Disclosures Conflict-of-interest disclosure: C.L.B. declares no competing financial interests. A.Y. has received research funding from Gilead, Novartis, Curis, and Johnson and Johnson and has received honoraria from Seattle Genetics, Gilead, Novartis, and Sanofi. Off-label drug use: Emerging treatment strategies using brentuximab vedotin, PI3K inhibitors, HDAC inhibitors, and ibrutinib in patients with HL.

Correspondence Anas Younes, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 330, New York, NY 10065; Phone: 212-639-7715; Fax: 646-422-2291; e-mail: [email protected].

References 1. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18): 2183-2189. 2. Sasse S, Rothe A, Goergen H, et al. Brentuximab vedotin (SGN-35) in patients with transplant-naive relapsed/refractory Hodgkin lymphoma. Leuk Lymphoma. Published online ahead of print March 27, 2013. doi:10.3109/10428194.2013.775434. 3. Bartlett N, Brice P, Chen RW, et al. Retreatment with brentuximab vedotin in CD30-positive hematologic malignancies: a phase II study [ASCO Annual Meeting Abstracts]. J Clin Oncol. 2012;30(15):Abstract 8027. 4. Rothe A, Younes A, Reiners EKS, et al. A phase I study with the bispecific anti-CD30 x anti-CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma [abstract]. Blood (Annual Meeting Abstracts). 2011; 118(21):624. 5. Younes A, Oki Y, McLaughlin P, et al. Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood. 2012;119(18):4123-4128. 6. Kasamon YL, Jacene HA, Gocke CD, et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012; 119(18):4129-4132. 7. Freedman AS, Kuruvilla J, Assouline S, et al. Clinical activity of lucatumumab (HCD122) in patients (pts) with relapsed/ refractory Hodgkin or non-Hodgkin lymphoma treated in a phase Ia/II clinical trial (NCT00670592) [abstract]. Blood (ASH Annual Meeting Abstracts). 2010;116(21):284. 8. Smith SM, Schoder H, Johnson JL, Jung SH, Bartlett NL, Cheson BD. The anti-CD80 primatized monoclonal antibody, galiximab, is well-tolerated but has limited activity in relapsed Hodgkin lymphoma: Cancer and Leukemia Group B 50602 (Alliance). Leuk Lymphoma. 2013;54(7):1405-1410. 9. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res. 2012;18(6):16111618. 10. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044-3051. 11. Westin JR, Chu F, Favad LE, et al. Phase II safety and efficacy study of CT-011, a humanized anti-PD-1 monoclonal antibody, in combination with rituximab in patients with relapsed follicular lymphoma [abstract]. Blood (ASH Annual Meeting Abstracts). 2012;120(21):793.

398

12. Kuppers R. New insights in the biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2012;2012:328334. 13. Meadows SA, Vega F, Kashishian A, et al. PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood. 2012;119(9): 1897-1900. 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(5):320-324. 15. Johnston PB, Pinter-Brown L, Rogerio J, Warsi G, Chau Q, Ramchandren R. Everolimus for relapsed/refractory classical Hodgkin lymphoma: multicenter, open-label, single-arm, phase 2 study [abstract]. Blood (ASH Annual Meeting Abstracts). 2012;120(21):2740. 16. Buglio D, Georgakis GV, Hanabuchi S, et al. Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines. Blood. 2008;112(4):1424-1433. 17. Lemoine M, Derenzini E, Buglio D, et al. The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines. Blood. 2012; 119(17):4017-4025. 18. Younes A, Copeland A, Fanale MA, et al. Safety and efficacy of the novel combination of panobinostat (LBH589) and everolimus (RAD001) in relapsed/refractory Hodgkin and nonHodgkin lymphoma [abstract]. Blood (ASH Annual Meeting Abstracts). 2011;118(21):118. 19. Hart S, Goh KC, Novotny-Diermayr V, et al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia. 2011;25(11): 1751-1759. 20. Derenzini E, Lemoine M, Buglio D, et al. The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. Blood Cancer J. 2011;1:e46. 21. Marzec M, Zhang Q, Goradia A, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008;105(52):20852-20857. 22. Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):32203224. 23. Blum KA, Johnson JL, Niedzwiecki D, Canellos GP, Cheson BD, Bartlett NL. Single agent bortezomib in the treatment of relapsed and refractory Hodgkin lymphoma: cancer and leukemia Group B protocol 50206. Leuk Lymphoma. 2007;48(7): 1313-1319. 24. Younes A, Pro B, Fayad L. Experience with bortezomib for the treatment of patients with relapsed classical Hodgkin lymphoma. Blood. 2006;107(4):1731-1732. 25. Fanale M, Fayad L, Pro B, et al. Phase I study of bortezomib plus ICE (BICE) for the treatment of relapsed/refractory Hodgkin lymphoma. Br J Haematol. 2011;154(2):284-286. 26. Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin Cancer Res. 2009;15(12): 3958-3969. 27. Buglio D, Mamidipudi V, Khaskhely NM, et al. The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism. Br J Haematol. 2010; 151(4):387-396.

American Society of Hematology

28. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239-245. 29. Kirschbaum MH, Goldman BH, Zain JM, et al. A phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: Southwest Oncology Group Study S0517. Leuk Lymphoma. 2012;53(2):259-262. 30. Zhou N, Moradei O, Raeppel S, et al. Discovery of N-(2aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor. J Med Chem. 2008;51(14):4072-4075. 31. Fournel M, Bonfils C, Hou Y, et al. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008;7(4):759-768. 32. Younes A, Oki Y, Bociek RG, et al. Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2011;12(13):1222-1228.

Hematology 2013

33. Younes A, Sureda A, Ben-Yehuda D, et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol. 2012;30(18):2197-2203. 34. Jona A, Khaskhely N, Buglio D, et al. The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors. Exp Hematol. 2011;39(10):1007-1017. 35. Younes A, Hernandez F, Bociek RG, et al. The HDAC inhibitor entinostat (SNDX-275) induces clinical responses in patients with relapsed and refractory Hodgkin’s lymphoma: results of ENGAGE-501 multicenter phase 2 study. [abstract]. Blood (ASH Annual Meeting Abstracts). 2011; 118(21):2715. 36. Fehniger TA, Larson S, Trinkaus K, et al. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011;118(19):5119-5125.

399

Novel therapy for Hodgkin lymphoma.

The treatment of Hodgkin lymphoma (HL) relies on multimodality treatment with standard chemotherapy, radiation therapy, and autologous or allogeneic s...
795KB Sizes 0 Downloads 0 Views