Leukemia & Lymphoma, 2014; Early Online: 1–9 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.876634

REVIEW

Recent advances in mantle cell lymphoma: report of the 2013 Mantle Cell Lymphoma Consortium Workshop Leo I. Gordon1, Steven H. Bernstein2, Pedro Jares3, Brad S. Kahl4, Thomas E. Witzig5 & Martin Dreyling6 1Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Chicago, IL,

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USA, 2University of Rochester Medical Center, Rochester, NY, USA, 3Hospital Clinic, University of Barcelona, Barcelona, Spain, 4University of Wisconsin, Madison, WI, USA, 5Mayo Clinic, Minnesota, MN, USA and 6University of Munich-Grosshadern, Munich, Germany

MCL-specific research grants and created the Mantle Cell Lymphoma Consortium (MCLC), a working group of more than 100 laboratory and clinical investigators from North America and Europe focusing on MCL. For the past 10 years, the LRF MCLC has convened a workshop in which MCL investigators are invited to present results of their MCLrelated studies and discuss current ideas and controversies in the field. The 10th MCLC Scientific Workshop was held on 24–25 April 2013, in Atlanta, Georgia. The workshop included sessions on MCL biology, prognostic markers, novel potential therapeutic targets, the role of stem cell transplant and recent and ongoing clinical trials. Highlights from the workshop are summarized in this report.

Abstract Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by overexpression of cyclin D1 resulting from the t(11;14) chromosomal translocation. MCL is biologically and clinically heterogeneous and frequently disseminates to extranodal areas. MCL remains a clinically challenging lymphoma subtype, as there is no proven curative therapy and no standard of care has been established for initial or subsequent lines of therapy. However, there have been considerable advances in the last several years in the treatment of MCL, leading to improved survival. Recent investigations into the biology of MCL, clinically relevant biomarkers, novel therapeutic targets and new treatment strategies were discussed at a recent workshop of the Lymphoma Research Foundation’s Mantle Cell Lymphoma Consortium. The presentations are summarized in this manuscript, which is intended to highlight areas of active investigation and identify topics for future research.

Proceedings

Keywords: Lymphoma and Hodgkin disease, immunotherapy, pharmacotherapeutics, marrow and stem cell transplant clinical results

State of MCL today In the opening presentation of the session, Pedro Jares, PhD (Hospital Clinic, University of Barcelona) reviewed the current state of MCL science. Dr. Jares noted that prior to the availability of genomics research, our understanding of the molecular biology of MCL was based on identification of the primary oncogenic event – the t(11;14) translocation – leading to elevated cyclin D1, and a few secondary genetic alterations affecting cell cycle and DNA damage response pathways. More recently, genomic studies have revealed that MCL is in fact clinically and biologically heterogeneous. Some MCLs are cyclin D1 negative, although they display similar genomic alterations. These cases display a differential miRNA profiling, and an important fraction of them carry CCND2 rearrangement [1,2]. Other studies have identified biomarkers that may be significant in MCL, including NOTCH1 mutations [3] and in the E3 ubiquitin ligase UBR5 [4]. Recent and ongoing research is correlating these biomarkers and expression profiles with clinical features

Introduction Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by cyclin D1 overexpression and the t(11;14) translocation. Outcomes for patients with MCL remain poor compared with other non-Hodgkin lymphoma subtypes. No curative therapy has been identified, and no standard treatment approaches have been established for initial or subsequent therapy. Recently, there have been substantial advances in the understanding of MCL biology, and clinical trials have demonstrated significant clinical activity with new treatment approaches. A central catalyst in MCL research has been the Lymphoma Research Foundation (LRF), which has provided

Correspondence: Leo I. Gordon, Northwestern University Feinberg School of Medicine, 676 N. St. Clair, Suite 850, Chicago, IL 60611, USA. Tel: 312-695-4546. Fax: 312-695-6189. E-mail: [email protected] Received 26 November 2013; revised 2 December 2013; accepted 10 December 2013

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of MCL to better understand how the disease may progress differently in different patients [5,6]. Dr. Jares provided an update on SOX11, a biomarker that has been a focus of extensive study in MCL. Recent research indicates that SOX11 may play a role in MCL lymphomagenesis by blocking terminal B-cell differentiation [7]. Together, this new information on the biology of MCL has led to a more complicated scientific model of MCL development that may help explain some of the variations in molecular and clinical characteristics of MCL that can be seen across patients. Eric Hsi, MD (Cleveland Clinic) discussed current practical issues regarding the pathology of MCL. The identification of cases of MCL not meeting conventional criteria has made the classification of MCL more complex. SOX11 has demonstrated utility for identifying patients with cyclin D1-negative MCL [8]. A non-nodal type of MCL is now recognized that is associated with a favorable prognosis [9], and in some cases may present with low-level blood or bone marrow involvement [10]. MCL in situ is a rare phenomenon characterized by the presence of MCL-like cyclin D1-expressing cells in the mantle zone, with no overt lymphoma [11]. Dr. Hsi also discussed recent efforts to identify prognostic factors in MCL [12] – information that could help guide risk stratification and selection of therapy in MCL. Michael Wang, MD (University of Texas, M. D. Anderson Cancer Center) provided an update on the investigational drug ibrutinib (formerly called PCI-32765), which has demonstrated significant efficacy in MCL. In an international, multicenter, phase II trial, ibrutinib demonstrated significant efficacy, with an overall response rate of 68%, including 21% complete responses, in patients with relapsed or refractory MCL. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8–not reached), the estimated median progression-free survival (PFS) was 13.9 months (95% CI, 7.0–not reached), and the median overall survival (OS) was not reached. The estimated rate of OS was 58% at 18 months [13]. Clinical trials with ibrutinib are ongoing, and in February 2013, the US Food and Drug Administration (FDA) granted ibrutinib a “Breakthrough Therapy Designation” intended to expedite the review time when the FDA filing for ibrutinib is made. (Note: Since the MCL workshop, on 13 November 2013 the drug was approved by the FDA for second-line treatment in MCL.) Dr. Wang also spoke about potential mechanisms of resistance to ibrutinib and novel strategies to overcome this resistance with new combination therapy approaches. Thomas Witzig, MD (Mayo Clinic) discussed the potential application of minimal residual disease (MRD) in the management of MCL. Currently, monitoring for MRD in MCL is restricted to clinical trials. In the Nordic Trial, which evaluated intensive front-line chemotherapy followed by autologous stem cell transplant (ASCT), the benefit of a 4-week regimen of rituximab (R) in MRD-positive patients was unclear [14]. However, Dr. Witzig noted that there have been advances in many facets of MCL treatment, including new induction and maintenance regimens, new active agents and refinements in MRD methodology that may lead to a new role for MRD monitoring. For example, a deep-sequencing

approach is being evaluated in B-cell malignancies that identifies clonal gene rearrangements at diagnosis, allowing monitoring of clonal evolution [15]. Another approach involves next-generation sequencing and real-time quantitative polymerase chain reaction (PCR) to detect MRD [16]. Dr. Witzig recommended that MRD monitoring be incorporated into all prospective trials in MCL, to better evaluate its role in MCL management. Brad Kahl, MD (University of Wisconsin) discussed the clinical trials in MCL currently being conducted by the United States cooperative groups. He provided an update on the randomized, phase II intergroup trial (S1106), which was initially comparing R-HyperCVAD-MTX/Ara-C (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine) induction followed by ASCT consolidation versus R plus bendamustine induction followed by ASCT consolidation in patients aged 65 or younger with previously untreated MCL. The HyperCVADcontaining arm was closed due to difficulty collecting stem cells from treated patients. Evaluation of the other arm is ongoing, and results from this study will provide important information on the use of R plus bendamustine followed by ASCT in younger patients. This trial is now closed. Another randomized, phase II intergroup trial (E1411) is comparing four different strategies for initial therapy of MCL in patients at least 60 years of age. Patients are being randomly assigned to bendamustine plus R with or without bortezomib, followed by maintenance R, either with or without lenalidomide. Martin Dreyling, PhD, MD (University of MunichGrosshadern) provided an overview of ongoing and future clinical trials in MCL being conducted by European researchers. For the initial treatment of patients younger than age 65, the MCL Younger 2 trial will evaluate an alternating regimen of R-DHAP (rituximab, dexamethasone, cytarabine and cisplatin) and R-CHOP (rituximab, cyclophosphamide, vincristine and prednisone) with experimental arms with or without ibrutinib as induction therapy. Patients will subsequently receive either ASCT (standard arm A), ASCT followed by R and ibrutinib maintenance (experimental arm B) or R and ibrutinib maintenance therapy only (experimental arm C). For patients older than age 65, the MCL Elderly R2 trial is comparing R-CHOP versus R-CHOP/Ara-C followed by maintenance R with or without lenalidomide. Finally, a company-sponsored trial is exploring bendamustine plus R with or without ibrutinib followed by R maintenance with or without ibrutinib. For relapsed disease, European researchers are evaluating R-HAD (rituximab, high-dose cytarabine and dexamethasone) with or without bortezomib. Other molecular therapies being evaluated for patients upon a second relapse, or those not qualifying for R-HAD, include ibrutinib or temsirolimus and a three drug combination of bendamustine, R and temsirolimus.

Pathology/biology Leticia Quintanilla-Martinez, PhD (University Hospital Tübingen) discussed her group’s research investigating the incidence of MCL in situ in the general population and in a cohort of patients with MCL with preclinical lymph node biopsies available. To assess the incidence of MCL in situ

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Mantle cell lymphoma workshop report in the general population, the investigators reviewed 1292 lymph node specimens obtained from 131 individuals over a 3-month period. The median age of the sampled individuals was 61 years, 60% were males and a mean of 5 lymph nodes were collected per patient. Of the 1292 lymph nodes sampled, no cases of MCL in situ were detected. Lymphatic tissues were also analyzed from 37 mainly extranodal samples tested from individuals who later developed MCL. MCL cells were detected in 10 samples (27%), including four patients (11%) with manifestations between 2 and 86 months before MCL diagnosis and six patients (16%) with small extranodal preclinical MCL infiltrates detected between 3 and 59 months before MCL diagnosis [17]. Virginia Amador, PhD (Institut d’Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Spain) presented results of molecular and cellular studies attempting to further elucidate the functional role of the neural transcription factor SOX11 in the development of MCL. In some studies, SOX11 has been shown to serve as a biomarker and one of the best discriminatory genes between conventional and indolent MCL tumors [5]. Dr. Amador and her colleagues have found that SOX11 directly regulates the expression of PAX5 – a transcription factor that maintains B-cell identity and represses plasma cell differentiation – and thus prevents MCL cells from completing their normal differentiation process. She and her colleagues proposed that the development of MCL may be due to the combination of cyclin D1 overexpression, deregulation of cell proliferation and the block of normal B-cell differentiation, which prevents further development throughout the SOX11–PAX5–BLIMP1 regulatory axis [7]. Elias Campo, MD, PhD (Hospital Clinic, University of Barcelona) presented results of studies investigating the potential role of somatic mutations in the biology of MCL. Previous sequencing studies have revealed frequent mutations in ATM, CCND1, TP53 and NOTCH1, and UBR5 in MCL cells [3,4]. Campo and colleagues have undertaken additional studies using next-generation sequencing to further characterize the somatic mutations associated with MCL. The investigators performed whole genome sequencing analysis on four cases of primary MCL and whole exome sequencing analysis on 29 cases of primary MCL and six MCL cell lines. The preliminary analysis shows that MCL genomes contained a mean of 1.2 mutations per Mb – higher than in chronic lymphocytic leukemia [18] but lower than in multiple myeloma [19]. MCL cells, particularly those with mutated immunoglobulin heavy chain variable gene (IgVh), demonstrated kataegis-like regional clustering of somatic mutations. These clusters were not always associated with structural variants. Campo and colleagues suggested that the genetic variability observed in MCL may be present at diagnosis and may become more pronounced over time as disease progresses and new subclones emerge. Pedro Jares, PhD (IDIBAPS, University of Barcelona) provided an update on his group’s investigations into the potential role of de novo DNA methylation changes in the pathogenesis of MCL and their clinical relevance [20]. Genome-wide CpG island methylation analyses were conducted on 132 primary MCL samples, six MCL cell lines and 32 normal lymphoid samples. In general, MCL cells displayed a more

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heterogeneous methylation pattern than normal cells, characterized most often by more extensive hypomethylation. The researchers identified hundreds of genes that were differentially methylated in at least 10% of MCL cells compared with normal cells, including 454 genes that were hypermethylated in MCL cells and 875 genes that were hypomethylated in MCL cells. Genes that were frequently methylated in MCL cells included inhibitors of the WNT pathway and tumor suppressor genes. In 22% of these genes, this hypermethylation was associated with significant down-regulation in mRNA expression. Jares and his colleagues also identified a subset of MCL samples with extensive CpG methylation that exhibited molecular characteristics of rapid cell growth that were significantly associated with a poor prognosis, including an increased proliferation signature and a higher number of chromosomal alterations. Samuel G. Katz, MD, PhD (Yale University School of Medicine) discussed his group’s progress in developing an animal model of MCL. A murine model for MCL has been elusive, as cyclin D1-transgenic mice demonstrate mildly impaired lymphocyte maturation [21]. Other work has shown that apoptotic defects such as BCL2 amplification and biallelic deletion of BIM are common in MCL cells [22]. Based on these findings, it has been hypothesized that MCL develops due to an unrestrained proliferative drive provided by overexpression of cyclin D1 in collaboration with a blockade in cell death due to the loss of BIM. In an attempt to recapitulate MCL, Katz and colleagues generated mice transgenic for cyclin D1 but lacking BIM in their B-cells. These mice exhibited lymphocytosis and splenomegaly and 12% developed cyclin D1-positive proliferations. Stimulation of the immune system in mutant mice induced MCL-like characteristics, including mediastinal lymphadenopathy, gastrointestinal lymphoproliferations, CD5 positive B-cells, splenic cyclin D1-positive B-cells and organ involvement of cyclin D1-positive cells. Thus, this new mouse model recapitulates significant genetic and histologic features of human MCL.

Prognostic clinical markers and treatment strategies (poster session) Issa Khouri, MD (University of Texas, M. D. Anderson Cancer Center) presented results from a clinical trial evaluating the addition of high-dose R to ASCT in 39 patients with MCL in first remission. R was administered during stem cell collection and at 1000 mg/m2 on days ⫹ 1 and ⫹ 8 after ASCT. After a median follow-up of 40 months the estimated 4-year OS and PFS rates were 82% and 59%, respectively. Continuous long-term remissions were reported in some patients; of the 16 patients alive and in complete remission at 36 months, 15 remained in remission after a median follow-up of 69 months. There was a significant association between risk of relapse after ASCT and Ki-67 level at diagnosis. Within the first 3 years, relapse occurred in 64% of patients with a Ki-67 level ⬎ 30% compared with 19% of patients with Ki-67 levels ⱕ 30% (p ⫽ 0.02). There was no significant association between use of high-dose Ara-C and relapse risk. The investigators noted that relapse rates were lower than those reported in historical controls of patients not receiving R. They concluded that the

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dose and schedule of R used in this setting should be evaluated in a randomized trial. Ryan Cassaday, MD (University of Washington, Fred Hutchinson Cancer Center) discussed results of an analysis investigating whether it is possible to predict which patients with relapsed/refractory MCL will benefit from ASCT. A model was developed based on outcomes in 67 patients who received ASCT for relapsed/refractory MCL. In this patient population, three factors were independently associated with the risk of relapse or death after ASCT. The first factor was the simplified MCL International Prognostic Index calculated at the time of autologous transplant (sMIPI-Auto). In a multivariate analysis, a sMIPI-Auto score of 3–7 was associated with a nearly three-fold increased risk of relapse or death compared with a sMIPI-Auto score of 1–2 (hazard ratio [HR], 2.9; 95% CI, 1.5–5.6; p ⫽ 0.002). The second significant factor was the presence of B-symptoms (HR, 2.7; 95% CI, 1.3–5.2; p ⫽ 0.005). The third factor was the “remission quotient,” calculated based on the months from diagnosis to ASCT divided by the number of prior therapies (HR, 0.7; 95% CI, 0.5–0.9; p ⫽ 0.02). Based on these three factors, patients could be stratified into favorable-risk and unfavorable-risk groups with substantially different predicted OS and PFS outcomes after ASCT. Dr. Cassaday noted that these findings needed to be validated in an independent group of patients. Thomas M. Habermann, MD (Mayo Clinic) provided an update on the mantle cell biomarker study from the University of Wisconsin and the University of Iowa/Mayo Clinic SPORE program utilizing the Molecular Epidemiology Research (MER) Database. Using samples from 57 individuals with MCL from the University of Wisconsin and 32 patients from the MER, this multi-institution study evaluated expression of 42 genes that may be prognostic in MCL with array-based quantitative nuclease protection assay on fixed tissue. Overall, three genes were identified that significantly predicted prognosis in the original group and in a 32-patient validation cohort: MYC, HPRT1 and CDKN2A. An additional three genes – TNFRSF10B, ASPM and SOX11 – were significantly prognostic in a combined analysis of all 89 patient samples. The investigators concluded that this type of analysis might be used to develop a prognostic test for individuals diagnosed with MCL. Kieron Dunleavy, MD (National Cancer Institute) presented results from a study evaluating bortezomib plus DAEPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab) followed by maintenance bortezomib versus observation in patients with newly diagnosed MCL. Of the 49 enrolled patients, 77% were male, the median age was 58 years (range, 41–73), 16% had blastoid-variant MCL and 14% had a high MIPI score. The addition of bortezomib to DA-EPOCH-R appeared to be feasible: 50% of patients developed at least grade 2 neurotoxicity and 33% of patients required bortezomib dose reductions or cessations. Grade 3/4 thrombocytopenia and febrile neutropenia were reported in 34% and 8% of cycles, respectively. The regimen appeared to be active: the 5-year PFS rate was 40%, which the investigators reported was higher than the 5-year PFS rate of 8% observed in a historical control group of 26 patients receiving DA-EPOCH-R without bortezomib.

Maintenance bortezomib did not appear to improve outcomes over observation. Accrual onto this study is continuing. Leslie Popplewell, MD (City of Hope) presented preliminary results of a phase I/II open-label, non-randomized study evaluating the safety and feasibility of adoptive T-cell therapy with central memory-enriched CD8 ⫹ T-cells following ASCT in patients with high-risk intermediate-grade B-cell nonHodgkin lymphoma (NHL). In the protocol, central memory T-cells are isolated from the peripheral blood prior to ASCT and genetically modified using a self-inactivating lentiviral vector to express a CD19-specific chimeric antigen receptor (CAR). The activated and modified CD8 ⫹ central memory T-cells are expanded in vitro, cryopreserved and infused into the patient on day ⫹ 2 or ⫹ 3 after ASCT. Thus far, five patients with diffuse large B-cell lymphoma have completed the protocol. The addition of modified T-cells did not appear to affect engraftment of cells following ASCT, and there were no significant additional toxicities over those expected with ASCT. The study is ongoing to determine the longevity of the modified cells and any effects of the T-cells on outcomes after ASCT. Martin Dreyling, MD, PhD (University of MunichGrosshadern) provided an update on results from the MCL Younger Trial, a study being conducted by the European MCL Network. The MCL Younger Trial previously showed that alternating courses of CHOP and DHAP plus R, followed by high-dose Ara-C and ASCT, induce more complete responses than six cycles of R-CHOP followed by ASCT [23]. Longer follow-up has confirmed the superiority of the Ara-C-containing regimen. After a median follow-up of 51 months, the Ara-C-containing regimen was significantly more effective than CHOP alone as assessed by median time to treatment failure (88 vs. 46 months; p ⫽ 0.0382), median duration of remission after ASCT (84 vs 49 months; p ⫽ 0.0001) and median OS (not reached vs. 82 months; p ⫽ 0.045). Adverse events during induction therapy were comparable, aside from higher rates of grade 3/4 hematologic toxicity, renal toxicity and grade 1/2 nausea and vomiting. Based on these outcomes, Dreyling and colleagues suggested that a high-dose Ara-C-containing induction regimen followed by ASCT should be the standard of care in patients younger than age 65. Elliot Epner, MD, PhD (Penn State Hershey Cancer Institute) provided an update on a phase I/II study evaluating a combination of epigenetic and immunotherapeutic agents for the initial treatment of MCL. Previous studies have demonstrated in vitro synergy with cladribine, an inhibitor of DNA and histone methylation, and a histone deacetylase (HDAC) inhibitor [24]. Moreover, the combination of cladribine and R has demonstrated activity in patients with indolent B-cell malignancies, including MCL [25,26,27]. Combining these approaches, the study evaluated a threedrug combination regimen including two agents that exert epigenetic effects – cladribine and vorinostat – plus rituximab in patients with previously untreated MCL. The regimen (“Epnergenetic therapy”) showed significant efficacy in the 38 treated patients, with an overall response rate of 100%, including 84% complete responses. Adverse effects were primarily low blood counts. Responses appear to be durable

Mantle cell lymphoma workshop report to date. Potential mechanisms of resistance were identified, including the cyclin D1-A polymorphism that confers nuclear localization of cyclin D1 and predicts for the “blastic phenotype.” In addition, failure in the central nervous system (CNS) because of lack of penetration of R was identified as well as an epigenetic mechanism of resistance outside the CNS involving down-regulation of CD20 mRNA. Dr. Epner concluded that the regimen warrants further study in larger, randomized trials and should be considered in older patients as first-line therapy both as part of clinical trials and off trial as per National Comprehensive Cancer Network (NCCN) guidelines.

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Developmental therapeutics Kai Fu, MD, PhD (University of Nebraska Medical Center) discussed the feasibility of using cell metabolism as a therapeutic target in MCL. He noted that in vitro treatment of tumor cells with metformin leads to increased glucose consumption and lactate production, suggesting that cells adjust energy metabolism by up-regulating glycolysis [28]. This up-regulation in glycolysis can be prevented by administering the modified glucose molecule 2-deoxy-d-glucose (2-DG), which inhibits glucose transport and phosphorylation, thereby reducing the output from glycolysis and the pentose phosphate pathway. To evaluate the antitumor activity of these agents targeting cell metabolism, Fu and colleagues administered 2-DG and metformin to aggressive B-cell lymphoma cell lines. The combination appeared to have antitumor activity against lymphoma cells by depleting cellular adenosine triphosphate (ATP), inhibiting cell cycle progression and promoting apoptosis. Moreover, exposure of lymphoma cells to 2-DG and metformin was found to inhibit activity of mammalian target of rapamycin (mTOR) by preventing its relocation to lysozyme surfaces. Administration of 2-DG and metformin also suppressed tumor growth in vivo in a xenograft lymphoma model. In animals, the regimen showed no apparent toxicity. Robert Baiocchi, MD, PhD (The Ohio State University) presented research investigating the feasibility of targeting the protein arginine methyltransferase (PRMT) enzyme in MCL. The PRMT enzymes are major regulators of protein function and signaling, transcription control, RNA metabolism and DNA repair [29]. One of the PRMT enzymes, PRMT5, has gained particular interest as it is overexpressed in hematologic malignancies, including MCL, and it is required for growth of MCL cell lines [30]. Overexpression of PRMT5 is regulated by repression of miR92b/96, and restoration of miR96 reverses PRMT5 dysregulation. A series of novel PRMT5 inhibitors have been designed and are being evaluated in preclinical studies by Dr. Baiocchi’s laboratory at the Ohio State University. PRMT5 inhibition has demonstrated in vitro antitumor activity against a variety of hematologic malignancies, including in MCL cell lines and primary MCL tumors, and appears to restore regulatory pathways involved in cell cycle progression, microenvironment signaling and apoptosis. L. Kyle Brett, MD (University of Virginia School of Medicine) presented results of studies evaluating new potential therapeutic combinations incorporating the Bruton’s

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tyrosine kinase (BTK) inhibitor ibrutinib. MCL cell lines were exposed to increasing doses of ibrutinib with a variety of secondary drugs, including drugs that act both within and outside the B-cell receptor pathway. Combinations that appeared to be synergistic based on induction of cytotoxicity were identified. Numerous agents targeting kinases within the B-cell receptor pathway did not synergize with ibrutinib; however, the proteasome inhibitors carfilzomib and bortezomib and the Bcl-2 inhibitor ABT-199 were synergistic with ibrutinib. The synergy between BTK inhibition and proteasome activity has been corroborated in other recent studies [31]. Jianguo Tao, MD, PhD (H. Lee Moffitt Cancer Center) discussed studies investigating the potential mechanism of microRNA dysregulation in aggressive B-cell lymphomas. MicroRNA dysregulation is associated with lymphoma cell survival, lymphomagenesis and disease progression. In vitro studies indicate that c-Myc represses miRNA transcription [32]. Tao and colleagues found that in aggressive NHL cells, including MCL, Myc can repress expression of the microRNAs miR-15a/miR-16-1 through recruitment of HDAC3 [33]. Additional work showed that miR-29 is repressed by Myc through interactions with both HDAC3 and the enzyme EZH2 [34]. Silencing of Myc with a small-molecule inhibitor has been found to restore miR-26a expression and suppresses growth of lymphoma cell lines [35]. Shantaram Joshi, PhD (University of Nebraska Medical Center) discussed a novel strategy for therapy-resistant MCL involving targeting of both nuclear factor-κB (NF-κB) and mTOR, two pathways that are constitutively active in MCL. A novel oral compound, 13–197, has been developed that inhibits the IκB kinase, a regulator of both NF-κB and mTOR. The activity of 13–197 was assessed in MCL cell lines derived from different tissue sites of mice with therapy-resistant MCL, generated as previously described [36]. The IκB kinase inhibitor suppressed the proliferation of therapy-resistant MCL cells and induced apoptosis. Molecular analyses confirmed that 13–197 perturbed NF-κB signaling and inhibited activation of the mTOR pathway. Treatment of primary MCL cells with 13–197 also inhibited proliferation and induced apoptosis. Studies were also conducted evaluating the effect of 13–197 in NOD-SCID (non-obese diabetic-severe combined immune deficiency) mice bearing therapy-resistant MCL. The compound demonstrated single-agent activity, reducing tumor burden and increasing survival in this animal model. Richard Jones, PhD (The University of Texas, M. D. Anderson Cancer Center) presented results of studies evaluating the novel tryptamine derivative JNJ-26854165, which activates p53 and acts as a HDM2 ubiquitin ligase antagonist. Jones and colleagues showed that treatment of lymphoma cell lines with JNJ-26854165 induced S-phase cell cycle arrest and caspase 3-mediated cell death, independent of p53 status. Investigations into the mechanism of JNJ-26854165 showed that the compound inhibited cholesterol transport, resulting in a morphology similar to that observed in lysosomal storage disorders. Molecular studies found that the compound inhibits cholesterol transport within the cells and degrades the high-density lipoprotein (HDL) cholesterol transporter

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ABCA1. This locks cholesterol inside the cells, causing cholesterol overload and cell death. Selina Chen-Kiang, PhD (Weill-Cornell Medical College) provided an update on studies evaluating the novel cyclindependent kinase (CDK)4/6 inhibitor PD0332991. ChenKiang and colleagues proposed that inhibition of CDK4/6 in MCL cells may sensitize them to the effects of a partner drug. To evaluate this hypothesis, the investigators conducted a phase I study in which patients with relapsed MCL received PD0332991 in sequential combination with bortezomib. The compound appeared to have clinical activity in this combination therapy. The scientists have been conducting functional genomic analyses of MCL cells isolated serially from patients to identify genes that may be associated with responses to, or resistance to, PD0332991. These studies may help elucidate genome-based biomarkers for targeting CDK4/6 in mechanism-based combination therapy in MCL.

Preclinical immunotherapy Bijal Shah, MD (H. Lee Moffitt Cancer Center) discussed progress toward development of a therapeutic agent targeting HDAC6. Shah and colleagues had previously shown that inhibiting HDAC6 increases immune reactivity and inhibits growth of MCL cells. A clinical-grade HDAC6 inhibitor ACY1214 (rocilinostat) has now been developed and is being studied in clinical trials in blood cancers. Dr. Shah noted that there might be a rationale for combining an HDAC6 inhibitor with ibrutinib through down-regulation of STAT3 [37,38]. Early preclinical studies suggest that a combination approach may enhance the kinetics and depth of response. Studies of the combination are ongoing. Thomas Tedder, PhD (Duke University Medical Center) provided an update on his group’s studies investigating the potential role of regulatory B10 cells in MCL. This infrequent subset of regulatory B-cells produces IL-10 exclusively and has demonstrated potent negative regulation of inflammation and autoimmunity in animal models [39,40]. A comparable B10 cell subset has also been identified in human blood [41]. Tedder and his colleagues have found that some human MCL and chronic lymphocytic leukemia (CLL) cells mimic B10 cells, produce interleukin-10 (IL-10) in response to specific signals and potentially induce immunosuppression that can negatively influence immunotherapy [42, and unpublished results] Remarkably, signals that normally regulate normal B10 cell IL-10 production can also influence malignant B-cell IL-10 production, suggesting that some B-cell tumors retain a dynamic ability to negatively regulate immune responses. Shruti Bhatt, MS (University of Miami) reviewed laboratory studies evaluating the effects of a novel “fusokine” physically linking IL-21 with an anti-CD20 antibody. IL-21 signaling is known to up-regulate c-Myc and induce apoptosis of DLBCL cells [43]. Bhatt and colleagues showed that MCL cell lines also express the IL-21 receptor, suggesting that MCL cells may also be sensitive to the effects of IL-21. In vitro treatment with IL-21 induced apoptosis in some, but not all, MCL cell lines and primary MCL cells. Mechanistic studies suggested that in the IL-21-responsive MINO cell line, IL-21-induced apoptosis is dependent on cMYC, Bax and signal transducer

and activator of transcription 3 (STAT3). Additional studies showed that IL-21 up-regulated cMyc in sensitive, but not resistant, MCL cell lines and primary tumor cells. Similarly, IL-21 has been shown to up-regulate cMyc in IL-21 sensitive, but not resistant, DLBCL cell lines [42]. Several studies have reported that IL-21 augments antibody-dependent cellular cytotoxicity (ADCC) induced by immunotherapy [44.45]. Thus, Bhatt and colleagues created a fusion protein linking IL-21 with anti-CD20 and have been characterizing the antitumor effects of the fusion protein. The fusokine triggered cell death of MCL cell lines and was able to overcome resistance to IL-21. The fusokine also induced greater ADCC compared with unfused IL-21 plus anti-CD20.

Debating the use of stem cell transplant High-dose chemotherapy with ASCT in first remission is an important component of treatment for some patients with MCL. However, there are many factors to weigh when deciding whether a transplant is appropriate for individual patients. To discuss these issues, two workshop participants engaged in a formal debate on the role of stem cell transplant in patients with newly diagnosed MCL. Mitchell R. Smith, MD, PhD (Taussig Cancer Institute, Cleveland Clinic) was assigned to argue in favor of an up-front transplant and Koen van Besien, MD (Weill-Cornell Medical College) was assigned to argue against the use of transplant. Illustrating the validity of both sides of the issue, Dr. Smith and Dr. van Besien made the case for the side opposite their actual clinical experience. Arguing in favor of transplant as part of the overall initial treatment strategy in selected patients, Dr. Smith noted that several ASCT strategies have shown long-term benefit in clinical trials. A small early trial of high-dose sequential chemotherapy with in vivo R-purged stem cell autografting demonstrated long-term remissions, with OS and event-free survival (EFS) rates of 89% and 79%, respectively, at 54 months [46]. More recently, the Nordic MCL2 and Groupe d’Etude des Lymphomes de l’Adulte (GELA) reported results of phase II trials evaluating CHOP and high-dose Ara-C regimens plus R followed by ASCT in MCL [47,48]. In the GELA trials, with median follow-up of 67 months, the strategy showed longterm efficacy, with a median EFS of 83 months and a 5-year OS rate of 75%. Although some data have shown a benefit with transplant regardless of the induction therapy used [49], the MCL Younger trial showed that that a high-dose Ara-Ccontaining induction regimen was superior to CHOP alone [23]. Dr. Smith pointed out that new approaches are being evaluated to further enhance the benefit of ASCT, such as the use of R before transplant. Arguing against transplant, Dr. van Besien focused on the significant toxicity of the procedure, which in some cases is fatal. In the Nordic MCL2 trial, the incidence of treatmentrelated deaths was 4.4% [48]. The potential benefits of the procedure for inducing remission of MCL must be weighed against the potentially serious toxicity of the therapy. He noted that the risks of transplant-related mortality and secondary cancer increases as patients age. Dr. Van Besien also pointed out that although transplant can induce remissions, late relapses sometimes occur. In the Nordic MCL2

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trial, although median OS and response duration exceeded 10 years, some relapses were reported more than 5 years after the end of treatment [48]. Dr. Van Besien noted that there can be issues regarding the feasibility of the transplant. There can also be issues with stem cell mobilization; for example, HyperCVAD has been associated with poor mobilization of peripheral blood stem cells [50], although others have reported that this can be circumvented by using early chemotherapy cycles for mobilization [51]. Both speakers agreed that allogeneic stem cell transplantation is not often appropriate in the treatment of MCL in first remission due to a lack of suitable donors, patient age and comorbidities, and a substantial increase in toxicity over autologous transplant. However, for selected younger patients with suitable donors, this remains a viable treatment option.

Keynote address: Bcl-2 as a therapeutic target The workshop’s keynote speaker was Anthony G. Letai, MD, PhD, Associate Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute in Boston. In his presentation, entitled “Bcl-2 as a therapeutic target,” Dr. Letai discussed Bcl-2 dependence, the use of BH3 profiling to identify Bcl-2 dependence, the potential clinical application of BH3 profiling and the significance of mitochondrial priming in cancer therapy. Dr. Letai noted that cellular dependence on antiapoptotic proteins correlates with their sequestration of activator BH3only proteins such as BID and BIM [52]. There is variability in the interactions between individual antiapoptotic Bcl-2 family members (Bcl-2, Bcl-XL, MCL-1, BFL-1 and BCL-w) and different BH3 peptides. The variability in these interactions can be detected using an assay that assesses mitochondrial sensitivity, revealing patterns of interactions between the different Bcl-2 family members and BH3-only peptides [52]. A cell’s dependence on an apoptotic protein for survival can thus be decoded based on that cell’s pattern of mitochondrial sensitivity to the peptide panel. This process, called BH3 profiling, could help optimize cancer therapy based on the observed patterns of sensitivity. Application of BH3 profiling to a panel of lymphoma cell lines showed that the technique can identify Bcl-2-dependent cells and predict sensitivity to the Bcl-2 antagonist ABT-737 [53]. BH3 profiling also predicts sensitivity to conventional chemotherapy agents [53]. The differential sensitivity to chemotherapy observed among different cancer cells may relate to differences in mitochondrial priming. Indeed, an analysis of acute myelogenous leukemia cells found that mitochondrial priming as measured by BH3 profiling correlates with responses to therapy and requirement for allogeneic transplant [54]. Letai and his colleagues proposed that Bcl-2 inhibition, or other types of targeted therapy, could serve to selectively prime cancer cells, making them more sensitive to the effects of chemotherapy. Thus, a strategy proposed by Dr. Letai for optimizing responses to cancer therapy involves obtaining a tumor sample from a patient, testing it in the laboratory to identify the best targeted therapy candidate, selectively priming the cancer cells with targeted therapy, and then following up with chemotherapy to maximize killing of cancer cells.

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Finally, Dr. Letai and colleagues have investigated the use of BH3 profiling for predicting responses to targeted therapy. In “dynamic BH3 profiling,” tumor cells are collected from a patient and treated with a panel of drugs. BH3 profiling is then performed, identifying which targeted agents generate the greatest change in mitochondrial priming. This type of analysis could allow personalization of therapy based on the greatest observed functional benefit.

Summary The 2013 MCLC Scientific Workshop highlighted the significant progress that has been made toward the understanding of MCL biology, the identification of clinically significant biomarkers and the development of effective therapies. Recent clinical trials have shown significant activity with new treatment approaches, and molecular studies are identifying potential ways to further improve upon those findings through the use of combination strategies and personalized, risk-stratified therapy. These advances in MCL will likely be relevant to other lymphoma and cancer types.

Acknowledgements The authors thank Melinda B. Tanzola, PhD and LRF staff members Kathleen Brown, MPA, CAE and Whitney Steen, MFA for assistance in drafting the proceedings of this meeting. This meeting, as well as some of the projects presented, was supported by grants from the Lymphoma Research Foundation Mantle Cell Lymphoma Initiative and the MCL Consortium. Meeting support was provided by the LRF and by Celgene Corporation, Janssen, Millennium: The Takeda Oncology Company and Pharmacyclics. The work summarized in this report has been supported in part by LRF Mantle Cell Lymphoma Initiative grants. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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