Clinical, Laboratory Advances Highlighted at 2018 Mantle Cell

Summer 2018

Clinical, Laboratory Advances Highlighted at 2018 Mantle Cell Lymphoma Workshop convening leaders in the field across a wide range of research environments, funding innovative studies and creating needed resources. Programmatic efforts of the MCLC include MCL investigator research grants, establishment of an MCL cell bank that contains research tools available for conducting laboratory research, patient education programs and the Focus on Lymphoma app, and the biennial MCL Scientific Workshop. This report provides an overview of each presentation given at the LRF Scholars attend the 2018 MCL Workshop (L to R): 2015 Scholar Victor Yazbeck, MD Virginia Common- 13th MCL Scientific Workshop and identifies wealth University, Meghan Gutierrez, LRF CEO, 2016 Scholar Lapo Alinari, MD, PhD, The Ohio State University, key emergent themes. 2018 Scholar Shalin Kothari, MD Roswell Park Comprehensive Cancer Center, 2016 Scholar Connie Batlevi, MD, PhD, Memorial Sloan Kettering Cancer Center, and 2014 Scholars Jonathon Cohen, MD, Emory Universi- “The Lymphoma Research Foundation’s MCL ty and Anita Kumar, MD, Memorial Sloan Kettering Cancer Center. The 2018 Scholar class is profiled on pg. 3. Consortium and its Scientific Workshop have n April 26 and 27, 2018, nearly 100 deliberate communication between scien- been key contributors to the advancement of O lymphoma researchers gathered tists and clinicians across this wide scope our understanding of MCL both clinically and in Atlanta, Georgia, for the Lymphoma of research is unique to this forum and the biologically,” says Thomas M. Habermann, Research Foundation’s (LRF) 13th Mantle cross-pollination between research fields MD, of Mayo Clinic, Chair of the Foundation’s Cell Lymphoma (MCL) Scientific Workshop. spanning from the laboratory bench to the Scientific Advisory Board. “It is gratifying that This biennial gathering includes LRF MCL patient bedside accelerates the understand- in its 13th incarnation the presentations are Consortium members, MCL grantees, and ing and development of treatment for MCL. as innovative and cutting edge as in the first scientists from the United States, Canada, years of the program.” and Europe, and provides an opportunity The MCL Consortium (MCLC), established [CONTINUED ON PAGE 2] for the world’s leaders in both laboratory by the LRF in 2005, includes more than “The MCL Consortium and its and clinical MCL research to share research 100 MCL researchers from North America Scientific Workshop have been key findings, discuss recent and ongoing clinical and Europe. The Consortium is designed contributors to the advancement of our trials, and strategize on the critical next steps to accelerate developments in the understanding of MCL both clinically to advance MCL research. Concentrated and understanding and treatment of MCL by and biologically.”

FEATURED IN THIS ISSUE: Profiles of 2018 LCRMP and MCL Grantees Page 3

Recipients of the Foundation’s MCL Therapeutic Studies Grant, as well as the 2018 class of the Lymphoma Clinical Research Mentoring Program (including Priyanka Pophali, MD, of Mayo Clinic, pictured left) explain their LRF-funded research. lymphoma.org 1 LETTER FROM THE CEO

Dear LRF Friends and Supporters, This past April, the Lymphoma Research Foundation (LRF) hosted its 13th Mantle Cell Lymphoma (MCL) Scientific Workshop. In our role as a pivotal convener of events involving key issues in lymphoma research, LRF is proud that this event remains an impactful one for the lymphoma research community, with over thirty presentations on cutting edge basic, translational, and clinical research in MCL presented to nearly 100 researchers from across North America and Europe. In this issue of Research Report, we present a summary of the Workshop’s proceedings, beginning on page 1.

In this issue, we also conclude our profiles of our 2018 research grantees, with our MCL Therapeutic Grant and Lymphoma Clinical Research Mentoring Program (LCRMP) recipients, beginning on page 3. If you missed coverage of our Clinical Investigator Career Development Award, Postdoctoral Fellowship Grant, and AYA Lymphoma Correlative Grant recipients in the Spring issue, please visit lymphoma.org/researchreport.

Your support of LRF’s mission allows us to continue to promote collaboration and innovation in lymphoma research through our grants and scientific workshops. If you are specifically interested in MCL research, please see page 15 for a way to maximize that support. Thank you for your part in helping the Foundation support all those affected by this disease.

Sincerely,

Meghan Gutierrez Chief Executive Officer

as analytic capabilities as an important contributor to ongoing MCL Workshop discovery. [CONTINUED FROM PAGE 1] The 2018 workshop included 33 original research presentations MCL Biology on a broad range of topics important in the understanding and Moderator: Leticia Quintanilla-Fend, MD, University Tuebingen treatment of MCL, including new findings from research on Scientists are continuing to develop their understanding of how MCL biology, recent research on novel pathways and potential dysregulation of particular genes or pathways impact overall sur- treatment targets, findings that improve understanding of vival (OS), sensitivity to treatment, and the potential for recurrent therapeutic resistance and personalization of therapy, presentation disease. This information builds our understanding of the pathways that can be targeted in development of new therapies. of MCL outcomes research, updates on prognostic and predictive biomarkers, and an update on recent clinical trials. The Keynote To open the session, Pedro Jares, PhD (Hospital Clinic Barcelona – Address, on circulating tumor DNA analysis for personalized IDIBAPS) discussed findings from his lab that show new potential lymphoma treatment, provided insight into the promise and roles of cyclin D1, a protein overexpressed in MCL that functions as potential limitations of the technology for non-invasive diagnosis a regulator of cell growth and division. In addition to its more well- and monitoring of MCL tumor genetics. known function as a cell-cycle regulator, cyclin D1 acts through a range of other pathways to control proliferation, cell differentiation, The research presented at the Workshop by laboratory scientists cell migration, and the DNA-damage response, among other func- and clinical researchers reflects the ongoing progress being made tions. When exploring the functional implications of cyclin D1 over- toward the LRF’s mission to eradicate lymphoma and serve those expression in MCL, researchers found that excess cyclin D1 causes an touched by this disease. Overall, researchers noted the remarkable overall decrease in gene expression through inhibition of transcrip- improvements in the nature and sensitivity of technologies as well tion. As the levels of cyclin D1 increase, overall RNA levels within the

2 Research Report NEW RESEARCH GRANTS

Foundation Announces Research Grants in Mantle Cell Lymphoma, Lymphoma Clinical Research Mentoring Program n conjunction with the Mantle Cell Lymphoma Scientific Workshop (see page 11). Both Dr. Dave and Dr. Tao will be profiled in IWorkshop, the Lymphoma Research Foundation announced two detail on the LRF website this summer. MCL Therapeutic Studies Grants, awarded to Sandeep Dave, MD, The Foundation also announced eight LRF Scholars, participants MS of Duke University and Jianguo Tao, MD of H. Lee Moffitt Cancer in the Lymphoma Clinical Research Mentoring Program (LCRMP). Center. As one of the world’s largest private funders of MCL research, Founded in 2014, the LCRMP brings fellows and junior faculty pursu- the Foundation has funded more than 50 grants for over $25 million ing lymphoma clinical research careers together with senior experts since inception of the MCL initiative in 2003. LRF grants have led in the field. The program begins with a week-long workshop where to important developments in the field, including the use of DNA Scholars work with expert clinicians, statisticians, and translational microarray technology to distinguish indolent and aggressive MCL, researchers to improve a clinical trial protocol and participate in models to predict prognosis, discoveries that further understanding discussions particular to a medical research career, such as preparing of treatment resistance in MCL, and the identification of biomarkers effective research publications and presentations, working with the that may permit more personalized treatment. This year’s funded NCI cooperative groups, finding (and later becoming) a mentor, and projects are expected to have an immediate impact on the under- working with LRF education and research programs. Scholars later standing of MCL’s biological mechanisms. participate in two follow-up programs, including attending a grant Dr. Dave is a Professor at Duke University and a member of LRF’s review meeting and presenting their research at the North American Scientific Advisory Board. His LRF grant project uses tissue samples Educational Forum on Lymphoma. This year’s Scholars are profiled collected as part of an NCI-Canada Intergroup Study in patients with beginning on page 4). previously untreated MCL. He and his colleagues will use the sam- “The Lymphoma Research Foundation’s Mantle Cell Initiative and its ples to assess biomarkers that can predict the clinical behavior of a associated research grants have been a key part of the Foundation’s patient’s disease when given standard therapies, in hopes of identi- portfolio for fifteen years and we are excited to see that program fying biomarkers that can predict whether a patient will respond to continue with these two innovative research projects,” says Meghan or be resistant to current frontline therapies in MCL. Gutierrez, the Foundation’s Chief Executive Officer. “Though the Dr. Tao is Professor at the University of South Florida College of Lymphoma Clinical Research Mentoring Program is our newest addi- Medicine and Senior Member at H. Lee Moffitt Cancer Center. His tion to the grants program, we are excited to see it continue to grow project seeks a greater understanding of the biological mechanism and attract the brightest early-career clinical researchers in lympho- behind ibrutinib resistance in MCL, with the goal of designing ma in its fifth year.” effective combination therapies to attack the mechanism causing Applications for the Foundation’s 2019 Grants Program, including the resistance and prolong ibrutinib’s effectiveness. His research the LCRMP, are now open. Visit lymphoma.org/grants for more on this topic prior to his LRF grant was presented at the 2018 MCL information. MCL Workshop be exploited in the development of future MCLs, indicating that disrupted function is therapeutics. in some way linked to the disease. To better [CONTINUED FROM PAGE 2] understand the contribution of ATM to the cell decrease. To elucidate the mechanism Maja Milanovic, PhD (Institute for Cancer pathogenesis of MCL, a mouse with the of this down regulation, Dr. Jares’ group Genetics, Columbia University Irving most common ATM mutation found in MCL looked at the regions of the genome where Medical Center) presented results of a lab- was generated. This particular mutation transcription is initiated, and found that oratory study on the role of ATM mutations negatively affects the functional properties cyclin D1 is often bound to these positions, in MCL pathogenesis. While characteristic of ATM kinase and mice show defects in where it physically interacts with the cellular of MCL, cyclin D1 overexpression alone T- and B- lymphocytes development that machinery that is responsible for initiating does not cause MCL, raising the question of are comparable to mice lacking ATM pro- transcription. Importantly, transcription can which the additional contributors are to the tein. However, mice with the mutated ATM be repressed to the point of lethality, indi- disease. ATM kinase is a protein that func- develop lymphomas much later than mice cating that cyclin D1 overexpression in MCL tions as part of the DNA damage response where ATM was missing entirely, indicating may sensitize cells to transcription inhibi- and mutations to its functional kinase that this particular mutation preserves tors. This “synthetic lethality” is one that may domain are present in up to 50 percent of [CONTINUED ON PAGE 8]

lymphoma.org 3 NEW GRANTEE PROFILES

Jennifer Agrusa, MD Elizabeth Brem, MD Baylor College of Medicine/ University of California, Irvine Texas Children’s Hospital LCRMP LCRMP

Investigating the Role of Telomeres in Hodgkin Lymphoma Breaking New Ground for Elderly Patients with DLBCL Telomeres, the DNA-protein structures attached to the ends of Elderly patients (age 75 and older) with diffuse large B-cell chromosomes, play an important role in protecting chromosome lymphoma (DLBCL) generally receive a lower level of chemotherapy integrity. Research suggests that significantly shortened telomeres than younger patients, because the intensity of chemotherapy may indicate an increased risk for developing specific diseases. Dr. and its side effects can take a greater toll on an elderly patient’s Agrusa and her colleagues have hypothesized that patients with body. However, less chemotherapy also leads to poorer outcomes Hodgkin lymphoma (HL) may be at risk for shortened telomeres for these patients. Dr. Brem and her colleagues are preparing to both because of the inflammation caused by HL in the human body conduct the first randomized clinical trial in the U.S. specifically for and the intensive therapy regimens commonly used to treat HL. Dr. elderly patients with newly diagnosed DLBCL. They will be testing Agrusa’s LCRMP project will study the role of short telomeres in HL, the addition of an oral therapy called CC-486 to the standard identifying how it may affect response to therapy, the development reduced level of chemotherapy and hope this extends patient of therapy-related toxicities, and HL pathogenesis. Once these roles survival rates without adding significant side effects. “Thirty-three are identified, Dr. Agrusa hopes her results will support upfront percent of patients 80 or older with DLBCL may not even get screening of HL patients to identify those who may need modified chemotherapy for a potentially curable disease,” Dr. Brem notes. “In treatment regimens or additional supportive care to counter the addition to trying to improve outcomes for these older patients, this effects of shortened telomeres. trial is an opportunity to learn how treatment affects these patients both long-term and short-term.” During Dr. Agrusa’s medical studies at New York University, she worked in NYU’s Late Effects Clinic, which treated cancer survivors Dr. Brem received her MD from the State University of New York dealing with the long term effects of their cancer diagnosis and (SUNY) at Buffalo, before a residency and fellowship at Beth Israel treatment. “Because of this experience, it has been my goal to min- Deaconess Medical Center in Boston. During college and medical imize toxicities and develop new ideas and techniques to improve school, she was fortunate to work with mentors who ran a transla- patients’ quality of life after treatment of pediatric cancer,” she says. tional laboratory specializing in lymphoma research. “Very early in After a residency at Children’s Hospital of Montefiore in the Bronx, Dr. my career, I did some pre-clinical experiments and helped analyze Agrusa began a fellowship at Texas Children’s Hospital/Baylor School specimens from patients on clinical trials to learn more about the of Medicine, where she is now an Instructor. During her fellowship, biology of the disease,” she says. She was prompted to apply to the she studied genetic factors that contributed to pulmonary (lung) LCRMP because of her interest in improving her skills as a clinical dysfunction in survivors of childhood HL. “While performing this researcher. “This is a different skillset than needed in the laboratory. research, I realized that there are a number of ways in which genetic It takes knowledge of trial designs and statistics, succinct but precise biomarkers can improve HL outcomes,” she notes, which prompted writing, leadership, and the ability to give a good presentation, just her LCRMP study and the future trajectory of her research. “The to name a few skills. [The LCRMP Workshop] is an incredible oppor- ultimate goal is to develop a strategy for screening HL patients for tunity to learn from some of the country’s best lymphoma investiga- relevant biological host factors, and to use these results to assist in tors and expand and refine my clinical trial skill set.” up-front stratification of patients.” Dr. Brem hopes to continue her career with further trials like her Currently working towards a Masters degree through Baylor’s LCRMP project as well as develop close working relationships with Clinical Scientist Training Program, Dr. Agrusa applied to the LCRMP laboratory colleagues to help translate research from the lab to the hoping to further enhance her progression towards a career as an clinic. She also hopes her success as a researcher ultimately helps her independently-funded translational physician-scientist. She notes patients. “One of the things that drew me to lymphoma and blood that the mentorship aspect of the program is also an important char- cancers is the depth and intensity of the doctor-patient relationship. acteristic. “I am extremely appreciative of those who are taking the I want to continue to have therapies to offer my patients; I don’t want time to develop a new generation of lymphoma clinical researchers to let them down!” through the LCRMP, and I am looking forward to gaining additional insight from them.”

4 Research Report NEW GRANTEE PROFILES NEW GRANTEE PROFILES

Jennifer Crombie, MD Brian Greenwell, MD Emory University/ Dana-Farber Cancer Institute Medical University of South Carolina LCRMP LCRMP

Investigating A New Combination Therapy for DLBCL and DHL Testing A New Combination Therapy for Older MCL Patients Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) Mantle cell lymphoma (MCL) is most commonly diagnosed in and double-hit lymphoma (DHL) often fail to respond to current patients age 65 and older. As a result, many MCL patients have therapies, leading to an urgent need for novel therapeutic options. difficulty tolerating some of the intensive therapies and stem cell Dr. Crombie’s LCRMP project will test the combination of the transplant that have been responsible for much of the improvement hypomethylating agent, azacitidine, with venetoclax (Venclexta), in MCL survival rates. The rise of therapies such as bendamustine an inhibitor of BCL-2, in patients with DLBCL or DHL. “While this and rituximab has helped some patients who need less intensive combination results in impressive responses in patients with AML therapies, but there is still room for improvement. Dr. Greenwell and [acute myeloid leukemia], the role of these drugs in lymphoma his colleagues want to combine bendamustine with two newer tar- remains unknown,” Dr. Crombie says. “Under the mentorship geted agents, obinutuzumab (Gazyva) and venetoclax (Venclexta). of Dr. Anthony Letai, I have generated data in the laboratory to Dr. Greenwell says,“We want to test this for therapeutic tolerability suggest that azacitidine enhances the activity of venetoclax in as well as for efficacy and disease control, including the ability to DLBCL and DHL cell lines, providing pre-clinical rationale to test control minimal residual disease (MRD; small amounts of lymphoma this combination in patients.” Recent genetic analyses have also that are not detectable with radiological techniques).” revealed that DLBCL is very heterogeneous. Dr. Crombie also plans Dr. Greenwell received his MD from the Medical University of South to test whether genetic profiling can help predict which patients are Carolina (MUSC), before a residency at Washington University most likely to respond to this combination as well as other targeted in St. Louis /Barnes-Jewish Hospital, and his fellowship at Emory therapies that are likely to be effective in this disease. University. He draws inspiration from his own patients as well as Dr. Crombie first became interested in lymphoma research during his own family. “My mother is a lymphoma survivor, having battled medical school at the University of Massachusetts while working in through progression and a bone marrow transplant from her sister. the laboratory of Dr. Andrew Evens (now at Rutgers Cancer Institute She is now doing well 30 years out from her transplant – and has and a 2018 LCRMP Co-Chair). As a Hematology/Oncology Fellow at been an instrumental part of who I am.” Dr. Greenwell also notes Dana-Farber Cancer Institute, she has further developed both her that the LRF’s support for his mentor, Dr. Jonathon Cohen (a partic- translational research skills under Dr. Letai and Dr. Margaret Shipp, ipant in the first LCRMP Workshop in 2014, as well as a 2016 Career and her skills as a clinical researcher, under Drs. Phillippe Armand, Development Award recipient) has indirectly provided benefit to his Matthew Davids, and LRF Scientific Advisory Board member Ann own career. “Dr. Cohen’s experience with LRF and subsequent career LaCasce. “My basic science and clinical research projects are comple- success have provided a groundwork and road map for my future mentary, as I have been identifying optimal combination therapies career success,” Dr. Greenwell says. “The LCRMP will now provide to use for the treatment of DLBCL, while also developing the frame- me an opportunity for critical review of current research and help to work to translate these treatments to the clinic,” she says, adding that improve my own future clinical research projects.” she hopes to ultimately become an independent, clinical investigator who also collaborates with laboratory-based investigators. In July 2018, Dr. Greenwell plans to return to MUSC as a faculty member. “I hope to develop a robust program in clinical investiga- Dr. Crombie sees her participation in the LCRMP as an “incredible tion at MUSC, building it much as mentors Drs. Christopher Flowers opportunity” to continue her development towards an independent (and LRF Scientific Advisory Board member) and Mary Jo Lechowicz career. “The LCRMP provides additional education in clinical trial built the program at Emory, and develop collaborations between development, specifically within the field of lymphoma, and valu- the clinic and labs based at MUSC’s Hollings Cancer Center.” Dr. able career development support from leaders within the field. This Greenwell further notes that his time at Emory with Dr. Cohen, Dr. program provides the framework to effectively design and imple- Flowers, and Dr. Kristie Blum, all of whom have been LRF Scholars or ment both my proposed project and other future clinical trials, and faculty in the LCRMP helped impress upon him the importance of to apply for future grant funding.” strong mentors in a medical research career. “I will continue to rely on their mentorship as well as other LRF leaders, and hopefully have the opportunity to ‘pass on’ the mentorship.”

lymphoma.org 5 NEW GRANTEE PROFILES

Shalin Kothari, MD Ryan Lynch, MD Roswell Park Comprehensive University of Washington Cancer Center LCRMP LCRMP

First-in-class therapy for mantle cell lymphoma Improving the efficacy of checkpoint inhibitors in HL Despite recent advances in available therapies, patients with the Checkpoint inhibitors such as pembrolizumab (Keytruda) have aggressive forms of mantle cell lymphoma (MCL) generally survive demonstrated some success in Hodgkin lymphoma (HL) by dis- less than a decade after their diagnosis. Dr. Kothari’s LCRMP project rupting a tumor cell’s expression of the protein PDL1. Although is testing the addition of pevonedistat, a first-in-class therapy tar- successful, complete remissions with pembrolizumab alone are geting the enzyme which activated the protein NEDD8. Working rare; Dr. Lynch and his colleagues are testing the combination of as an NEDD8-activating enzyme (NAE) inhibitor, Dr. Kothari pembrolizumab and a PI3K inhibitor, TGR-1202 in patients with believes adding pevonedistat to standard therapies rituximab and relapsed and refractory HL. “Inhibiting the PI3K protein may have ibrutinib will help slow cancer growth. “Cancer cells proliferate with a direct effect on the tumor cell as well as augment the immune the help of certain cellular proteins. Pevonedistat is a novel drug response against the tumor with pembrolizumab,” Dr. Lynch says. that triggers a self-killing mode in cancer cells (apoptosis) by para- Dr. Lynch received his MD from Boston University before a lyzing the processing of such proteins by a proteasome – essential- residency at Washington University in Saint Louis. During his ly a cellular internal garbage disposal system,” Dr. Kothari explains. residency, he became interested in lymphoma research through Having already published results showing that this combination his work with Dr. Kenneth Carson on a project involving diffuse has been effective and safe in a laboratory setting, Dr. Kothari and large B cell lymphoma (DLBCL) patients at Veterans Administration his colleagues hope a clinical trial will demonstrate that this combi- hospitals. His experiences on that project led in turn to a nation effectively prolongs survival for MCL patients. hematology/oncology fellowship at Stanford University, where he Dr. Kothari received his MD from Gujarat University in his native worked with Drs. Ranjana Advani (a current LRF Scientific Advisory India before a residency at State University of New York (SUNY) Board member) and Saul Rosenberg (an SAB Member Emeritus), Upstate and his fellowship at Roswell Park Comprehensive Cancer both leaders in the pioneering treatments for Hodgkin lymphoma. Center, where he is Chief Administrative Oncology Fellow. He cred- His LCRMP project was generated from Dr. Lynch’s desire to help its his mentor at Roswell Park, Dr. Francisco Hernandez-Ilizaliturri HL patients who don’t respond to current therapies. “Despite the with helping him shape and hone his research on this project. Dr. approval of three new drugs for HL in the past decade, long term Kothari further notes that in participating in the LCRMP, “the skillset cure still eludes many patients who relapse after initial therapy,” he that I acquired will help prevent common errors and challenges notes. faced by young physician-scientists, hindering their success. The Aiming for a career as an established clinical researcher in opportunity to participate in the multidisciplinary small groups lymphoma, Dr. Lynch hopes his participation in the LCRMP will aid with experts in the field also enhanced my achievement of these him in that goal through the mentorship from the program’s expert skills and milestones.” faculty. “Connections made through LRF will be critical in these Dr. Kothari intends to continue his career as an academic research- early stages of my career as I get involved in multicenter clinical er, noting that in ten years’ time he sees himself leading both trials and clinical research projects.” clinical and translational projects to support research efforts in Dr. Lynch finds hope in the approval of multiple new targeted lymphoma. He adds that the history of lymphoma treatment – therapies and immunotherapies for lymphoma, especially in with Hodgkin lymphoma achieving a cure in the 1960s – inspires what it means for patients with relapsed or refractory disease. him to push for further developments. “It was the perseverance “The recent approvals have shown that through the work of of researchers back then that led to the first breakthroughs. Now clinicians and patients on clinical trials, we can make progress in it is time for the current generation of oncologists to raise that bar, the treatment of lymphoma. For certain patients, particularly those push that envelope, and save more lives.” that have failed multiple therapies, even modest improvements can make a huge difference. “

6 Research Report NEW GRANTEE PROFILES NEW GRANTEE PROFILES

Priyanka Pophali, MD Patrick Reagan, MD Wilmot Cancer Institute Mayo Clinic, Rochester University of Rochester LCRMP LCRMP

Exploring the effects of exercise on outcomes for survivors Combating ibrutinib resistance in B-cell NHL and CLL Patients who achieve a complete remission of their lymphoma are Patients with B-cell Non-Hodgkin lymphoma (NHL) and chronic still at risk for additional health complications even if they do not lymphocytic leukemia (CLL) sometimes have a mutation in a gene relapse. Regular exercise has been demonstrated to reduce fatigue called TP53 that has been demonstrated to cause resistance to and improve quality of life in cancer survivors, but the exact effects chemotherapy treatments. “Since lymphomas in which this gene and degree of improvement has not yet been studied in lymphoma works normally can be treated effectively with chemotherapy, survivors specifically. Dr. Pophali’s LCRMP project will look at restoring its function could potentially enhance the ability to control changes in survivor exercise routines and their effect on patient these diseases,” Dr. Reagan notes. His LCRMP project will study a outcomes both through studying data in the Lymphoma Molecular therapy called APR-246, which binds to TP53 and has been shown Epidemiology Resource (MER) database, a resource developed in laboratory studies to restore normal function of that gene. Dr. by Dr. Pophali’s home institution, Mayo Clinic, and through a pilot Reagan and his colleagues will test a combination of APR-246 with study testing whether receiving a one-time exercise prescription ibrutinib in B-cell NHL and CLL patients who have mutated TP53, from their physician will impact survivors’ physical activity and, in the hopes that it will allow these patients to experience the full subsequently, their health outcomes. “If we are able to increase a effectiveness of ibrutinib and other standard therapies. “Effective survivor’s level of physical activity through a practical, one-time treatments for my patients who have TP53 mutations is a major exercise intervention that is tailored to the individual’s needs, it will unmet need and I wanted to pursue a clinical trial concept that could allow lymphoma survivors to play a proactive role in improving their possibly benefit this group,” he says. own outcomes,” Dr. Pophali notes. Dr. Reagan received his MD from State University of New York (SUNY) Dr. Pophali’s career in medicine was inspired by her father, a hema- Upstate Medical University, before a residency at the University of tologist/oncologist in their native India. She received her MBBS (an Virginia, where he served as Chief Resident, before a fellowship at MD equivalent degree) from Indira Gandhi Government Medical Wilmot Cancer Institute of the University of Rochester, where he is College in her native India before working as a research associate at currently an Assistant Professor of Medicine. The number of major the National Institutes of Health, where she studied long term com- scientific and therapeutic advances in lymphoma over the past plications in survivors of hematopoietic stem cell transplant. Later several years prompted Dr. Reagan’s interest in lymphoma research. as a resident at Cleveland Clinic, she began working on outcomes “I think that we are learning more about the biology of lymphomas for early stage Hodgkin lymphoma patients. Dr. Pophali continued and the reasons why our current treatments do not currently work to pursue her interest in lymphoma outcomes research with her well in certain patients,” he says. “As we continue to understand this, I current fellowship at Mayo Clinic. “As I got to know my patients in think that we will identify more therapies that are more effective and the continuity clinic, I realized that cancer is a life changing diagnosis hopefully have fewer side effects.” and impacts lives even after the disease has been cured,” Dr. Pophali says. “Research that understands survivorship issues and attempts Dr. Reagan’s interest in the LCRMP began as an interest in devel- to bring survivors’ lives closer to normal is a very worthwhile career oping connections with the faculty and his fellow Scholars in the endeavor for me.” program, as well as an interest in increasing his involvement with the Lymphoma Research Foundation. “Participating in the LCRMP Dr. Pophali’s participation in the LCRMP was prompted by a desire was exciting, and the feedback I received was critical to making my to better understand clinical trial design and how to navigate the trial as successful as it can be,” he says. “I hope to continue designing practical issues around conducting clinical studies. “I enjoyed getting early phase clinical trials for patients with high risk lymphomas, as to know colleagues outside my institution who share similar visions well as building collaborations with colleagues at my institution and for lymphoma patients and exposing myself to new ideas from col- throughout the country.” leagues who work on different aspects of lymphoma research,” she adds. “The skills and experiences I gained through the workshop will help me to further my career goal of contributing meaningfully to the field of hematology, particularly lymphomas.”

lymphoma.org 7 MCL WORKSHOP - KEYNOTE ADDRESS

Ash A. Alizadeh, MD, PhD, Delivers MCL Workshop Keynote Address

he Workshop’s keynote speaker was Ash Alizadeh, MD, PhD, will emerge as a valuable TAssociate Professor of Oncology at Stanford University. Dr. tool for tumor genotyping at Alizadeh discussed how MCL tumor DNA circulating in the blood- diagnosis, treatment selec- stream (ctDNA) collected through a “liquid biopsy” blood draw can tion and predicting response, be used to predict risk during monitoring for individual patients. monitoring, and early While tumor biopsies can provide helpful information, they are detection of relapse through invasive and are not without risk for the patient. Furthermore, biop- identification of emergent sies from a single site may not adequately capture tumor heteroge- MCL subclones resistant to neity. treatment. At each stage in the process, ctDNA analysis Early studies have validated the accuracy of ctDNA testing and can be used to generate a its capacity to predict treatment failure following transplant. Dr. continuous individualized Alizadeh provided an overview of how the technology has evolved Ash Alizadeh, MD, PhD of Stanford risk index (CIRI) that will per- to its current state, as well as how it can be used for more continu- University mit a more dynamic patient ous monitoring of cancer and to predict outcomes of treatments. assessment across tumor types. Dr. Alizadeh and his colleagues at Stanford helped develop one of these advances, called Cancer Personalized Profiling by Deep In addition to the in depth discussion of liquid biopsy, Dr. Alizadeh Sequencing (CAPP-Seq). This technology has helped improve the shared results of a study that used “peptidomic profiling” to identify sensitivity and predictive power of liquid biopsy for lymphomas protein antigens on the surface of MCL cells that may be used to and other tumors by following many mutations across more than immunize patients during remission so that if the MCL relapses, 300 genes. the cells will be recognized and destroyed by the immune system. Identifying these new antigens paves the way for new immuno- As technology continues to evolve, Dr. Alizadeh predicts that ctDNA therapies.

MCL Workshop than in conventional MCL (90 percent), the Mariusz Wasik, MD (University of [CONTINUED FROM PAGE 3] degree of kappa light chain restriction in Pennsylvania) presented a case study in CD5-negative MCL was higher, and IGHV which MCL is thought to have mutated and some ATM protein functions that may play mutation was seen in over 40 percent of changed into another type of malignancy, important roles in the late onset of MCL. CD5-negative MCL. Together, these results sarcoma. While this type of change, called Further research is underway to understand indicate that CD5-negative MCL may have transdifferentiation, has been reported in the the role of mutated ATM in mice that over- a unique biology, and that it may be suffi- past, the conversions described have been express cyclin D1, and to determine if ATM ciently different to prompt consideration of limited to those between closely related mutation in the MCL setting leads to a favor- a different treatment approach. To assess the immune cells. In this report, the conversion able response to selective chemotherapy. importance of CD5 in overall survival (OS), is to a much more distantly related cell type. Arshia Soleimani, MD (Tulane University) reports from 79 patients were evaluated and Here, the MCL patient was treated with discussed her research on the role of the the median OS for CD5-negative MCL was multiple diverse therapies over the course membrane protein CD5 in MCL. Though up found to be greater than 14 years, a substan- of twelve years, and eventually developed to ten percent of MCLs lack CD5 entirely, the tial difference from the historic OS for con- poorly differentiated sarcoma (PD-Sc). To function of this protein in MCL is unknown. ventional MCL of three to five years. Further determine if these two malignancies were In order to understand how the absence evaluation of these 79 reports showed that related, researchers compared the gene of CD5 contributes to clinical outcomes, this increase in OS was independent of other expression profiles, genome sequences, and more than 800 articles were screened and prognostic markers SOX11 and Ki-67, raising DNA methylation patterns of the patient’s 323 cases of CD5-negtative MCL reported the question of whether CD5 could be used early MCL, late MCL, and PD-Sc cells. The in the literature were analyzed. The pri- as an independent biomarker for indolent MCL and PD-Sc cells contained several simi- mary differences between CD5-negative MCL. While the exact role of CD5 remains lar genetic abnormalities, indicating that the MCL and conventional MCL were a lower unclear, this study highlights the need for two cell lines are more closely related than level of expression of SOX11 (44 percent) additional investigation. [CONTINUED NEXT PAGE]

8 Research Report MCL WORKSHOP - NOVEL PATHWAYS expected for cells from malignancies of 14.6 percent of relapse biopsies. Together, Lalit Sehgal, PhD (University of Texas MD independent origin. Most dramatic, how- these data support the hypothesis that Anderson Cancer Center) shared results ever, was the change in DNA methylation dysfunctional mutations in S1PR1 pro- from his research on the role of tumor pattern. DNA methylation represents motes retention of malignant MCL, thus microenvironment on relapsed and another layer of control in gene expres- preserving a “minimal residual disease res- refractory MCL. His research used the sion, termed epigenetic programming, ervoir” that later may give rise to a relapse. recently developed system for culturing, which can express or silence a particular or growing, primary MCL cells in the lab. Thomas Habermann, MD (Mayo Clinic) gene by changing whether the cell’s tran- This system requires that MCL cells be concluded the first session with a report scription machinery can access it. When co-cultured with mesenchymal stromal that identifies mutations within three comparing the MCL and PD-Sc cells, the cells (hMSC), supportive cells that also genes (TNFRSF25, TRAF5 and RELB) as patterns of gene methylation was widely reside in the bone marrow. Using this sys- genetic markers associated with overall variable, supporting the hypothesis that tem, Dr. Sehgal’s research group showed survival (OS) in MCL. These genes produce epigenetic reprogramming can permit that in the co-culture system, MCLs were proteins that comprise one of two overac- clonal malignant cells to differentiate into able to survive for four weeks, and that tive pathways in MCL, the tumor necrosis another malignancy. This transdifferenti- MCL-initiating cells (MCL-ICs) constituted factor (TNF) and nuclear factor-NF-kB (NF- ation permits these cells to escape initial one percent of the MCL population. Using kB) pathways. In an initial study, research- treatments, but can render them vulnera- this system, researchers identified the sig- ers analyzed 40 candidate genes in the ble to a different therapy designed to treat naling molecule FGFR-1 as important for DNA of 39 MCL patients in the NCI-SEER malignancies more closely related to the maintaining growth and survival of MCL dataset, and following adjustment for indi- new lineage. in the microenvironment. Importantly, vidual patient MIPI and treatment received FGFR-1 is known to be associated with Birgitta Sander, MD, PhD (Karolinska found that eight genes were associated poor overall and progression-free surviv- Institutet) described the clinical and with differences in OS. To verify these asso- al in R-CHOP-treated MCL. In this study, functional impact of S1PR1 mutations ciations, DNA from a larger group of 101 researchers showed that inhibition of in recurrent MCL. S1PR1 is expressed by patients from the Molecular Epidemiology FGFR-1 decreases growth and proliferation both normal mantle zone B cells and MCL, Resource (MER) of the University of Iowa and sensitizes MCL cells to chemothera- and is responsible for controlling the exit and Mayo Clinic Lymphoma Specialized peutic drugs. Identification of these signals of lymphocytes from the marrow to the Program of Research Excellence (SPORE) and their role in MCL-IC survival paves the blood and lymph in response to a chem- was analyzed, and the association with OS way for design of treatment that disrupt ical gradient of the S1PR1 ligand, SP1. In was retained by three of the eight genes MCL and potentially for curative treatment an initial analysis of 27 samples from 13 from the initial analysis. TNFRSF25 and strategies. patients, eleven of which were relapse TRAF5 mutation was found to be asso- biopsies, S1PR1 was found to be one of 25 ciated with inferior survival, while RELB Fengdong Cheng, MD (The George recurrent mutations. In an expanded study mutation was associated with superior Washington University) discussed research of over 200 samples, paired samples from survival. Together, these findings identify that led to identification of bromodomain 17 patients were analyzed, and in eight three genes that may be further evaluated (BRD)-specific inhibitors as a novel avenue percent of samples, S1PR1 was found to as drug targets and build understanding for targeting MCL. BRDs are architecturally be mutated; in each case, mutations were of MCL disease progression. distinct regions of proteins that often have such that expression or function of the a shared function. BRDs are present in a protein significantly diminished. In an MCL Novel Pathways and Targets wide range of proteins that “decode” the MCL cell line, diminished S1PR1 expres- Moderator: Elias Campo, MD, PhD, Hospital pattern of histone acetylation that controls sion resulted in reduced migration in Clinic de Barcelona gene expression. This type of epigenetic response to SP1. Researchers hypothesize Researchers continue to identify novel gene regulation is commonly disrupted that this effect is linked to MCL pathology pathways that can be targeted in the in MCL, leading researchers to explore treatment of MCL. As new pathways are because these S1PR1 mutated cells could the potential role of BRDs. In the research defined and the nuances of previously be retained in the supportive microenvi- recognized pathways are uncovered, presented by Dr. Cheng, inhibition of ronment of the tissue where they are less strategies for treatment may continue to BRD enhances the function of T-cells in susceptible to chemotherapy. In a recent evolve. the immune system, while leading to clinical trial S1PR1 mutations were present a decrease in expression of the protein in 5.9 percent of diagnostic biopsies and in [CONTINUED NEXT PAGE]

lymphoma.org 9 MCL WORKSHOP - PERSONALIZED THERAPY

MCL Workshop axis and the potential of PAK inhibition as Research efforts have led to new insights a promising strategy for enhancing sensi- on the drivers of disease heterogeneity [CONTINUED FROM PAGE 9] tivity to chemotherapy and other targeted in MCL and the events that lead to and PD-L1, which promotes MCL survival by maintain ibrutinib resistance. Together therapies in the treatment of MCL. immunosuppression. In addition, BRD inhi- these findings support research and bition increases the levels of inflammatory clinical trials that lead to more efficient Jimmy Lee, MD (The University of Chicago) markers. These two activities make MCL and effective treatment of MCL that is tai- discussed work on identifying the mech- lored to disease subtypes and eventually treated with BRD inhibitors more suscep- anisms of ibrutinib resistance in MCL. In to individual patient disease. tible to clearance by the immune system. spite of high clinical efficacy, nearly all These features make inhibition of BRD a Qian Zhang, MD, PhD (University of patients acquire ibrutinib resistance. In promising target for MCL therapies. Pennsylvania) presented a new cultured this study, comparison of gene profiles in MCL cell line that maintains key features of Elisabeth Silkenstedt, MD (University both sensitive and resistant MCL during primary malignant cells. This finding is of Hospital Ludwig Maximilian University treatment with ibrutinib confirmed known particular importance because when cells Munich) presented work on characteriza- mechanisms of resistance and also iden- are cultured in the lab, they often accu- tion of the impact of NOTCH1 mutations tified another gene, Myc, that fits the pat- mulate mutations or epigenetic changes in MCL. In addition to the overexpression tern of resistance. Researchers found that that render them of little practical use in of cyclin D1 characteristic of MCL, several knocking down Myc expression inhibited evaluating treatment efficacy. In this study, secondary genetic alterations are known MCL growth and induced cell death in concentrations of secreted cytokines, DNA to contribute to pathogenesis. Among ibrutinib-resistant cells. Researchers were methylation patterns, and gene mutation them, NOTCH1 is associated with shorter able to repeat this outcome when using an profile were maintained following extend- overall survival (OS) and is present in five antibody to inhibit an upstream protein, ed culture of the cell line in the lab. This cell to ten percent of MCL. Within this work, HSP90, indirectly inhibiting Myc. This dis- line, MCL-RL, contains several novel muta- researchers identified molecules that acti- covery revealed a new target for treatment tions and maintains a relevant sensitivity vate NOTCH1 in MCL and showed that the of ibrutinib-resistant MCL. profile to kinase inhibitors. Together, these NOTCH1-mediated enhancement of tumor Carrie Franzen, PhD (The University of findings support the use of MCL-RL cells in angiogenesis as well as several other path- Chicago) described research on the role of research exploring MCL physiology pro- ways that contribute to the aggressiveness Rac2 in cell adhesion and explained how viding another tool for further developing the disease can be inhibited by antibodies cell adhesion is connected to the consti- understanding of MCL. designed to inhibit NOTCH. Together these tutively (continuously) active B-cell recep- findings suggest that inhibition of the Seung-Cheol Lee, PhD (University of tor signaling in MCL. Ibrutinib works by NOTCH1 signaling pathway may provide Pennsylvania) discussed a novel method targeting B-cell signaling through Bruton effective treatment for a subset of patients for evaluating patient response to therapy. tyrosine kinase (BTK) inhibition and caus- with NOTCH1 mutations. Currently, response is evaluated by assessing a transient increase in the number of ing tumor volume using imaging, a meth- Chengfeng Bi, MD, PhD (University of cells that move from the lymphoid tissue od that is somewhat limited given that Nebraska Medical Center) presented the to the periphery. This shift is thought to be volume changes occur relatively late after Rac1-PAK axis as a potential novel thera- promoted by a reduction in the MCL cells’ effective inhibition of the targeted kinase. peutic target in MCL. The Rac1 protein is ability to adhere to the stroma (tissue). In clinical care, the inability to identify met- important for a number of cell adhesion In this work, researchers identified the abolic changes indicating that therapy is pathways and its overexpression in MCL proteins involved in mediating the con- effective prevents clinicians from stopping is associated with a poor clinical outcome. comitant reduction in BCR signaling and cessation of treatment that is ineffective or Depleting the expression of Rac1 in MCL adhesion. By identifying these proteins making informed, personalized addition of cells decreased cell proliferation and and their role in MCL, researchers have pro- therapies that target alternative pathways. increased sensitivity to chemotherapy vided an additional avenue for therapeutic In this study, by examining cell metabolic agents. In addition, when two “down- development. changes known to contribute to MCL, stream” proteins in the Rac1 pathway, PAK1 researchers were able to distinguish ibru- and PAK2, are inhibited, MCL sensitivity to MCL Therapeutic Resistance and tinib-sensitive and ibrutinib-resistant cells. chemotherapy was dramatically increased. Personalization of Therapy Moderator: Robert Baiocchi, MD, PhD, The This finding supports the use of imaging Future endeavors will focus on identifying Ohio State University that is capable of monitoring cell metab- the downstream signaling of Rac1-PAK [CONTINUED NEXT PAGE]

10 Research Report MCL WORKSHOP - OUTCOMES olism, as it may effectively determine the drug screening to tai- impact of treatment early and has the lor therapy to specific potential to identify drug-resistant cells patients. MCL is a com- and whether or not they may be effectively plex and heterogeneous targeted by alternative therapy. disease that has a wide range of genetic muta- Selina Chen-Kiang, PhD (Weill Cornell tions that are thought to Medicine) provided an update on studies shape susceptibility to exploring the therapeutic application treatment. While work of inhibiting the cell-cycle regulator to identify these net- cyclin-dependent kinase 4 (CDK4) in resis- works is informative for tant MCL. In previous laboratory studies, development of novel her team showed that inhibition of CDK4 therapies, their use in restored sensitivity of resistant MCL cells treatment selection is to ibrutinib. In this presentation, Dr. Chen- problematic. Instead, Kiang shared early findings from a phase I Diagram of the development of cancer therapy resistance. Illustration cour- MCL cells from patients tesy Jianguo Tao, MD, PhD, Moffitt Cancer Center. clinical trial in patients on the effect of ibru- can be tested for sensitiv- less of therapy. The findings from this study tinib and the CDK4 inhibitor palbociclib (a ity to a range of treatments provide a lens through which the results treatment used in breast cancer). Overall, by screening cultured cells prior to treat- of clinical trials may be viewed and may the response to treatment was rapid and ment. Using a tool called EMMA, Dr. Shah inform clinical practice. durable and the rate of relapse in patients and colleagues can test sensitivity to up who received the combination treatment to 127 drugs within five days. Sensitivity Dr. Habermann also presented findings was lower than patients who received ibru- predicted by EMMA correlates well with from a recent study on the impact of tinib or palbociclib alone. To learn more, observed clinical outcomes in patients, and autoimmune diseases such as rheumatoid a larger phase II clinical trial is currently may be a first step in personalized therapy arthritis or Crohn’s disease on treatment underway. selection based on cell response to treat- outcomes for MCL. Autoimmune con- Jianguo Tao, MD, PhD (H. Lee Moffitt ments in the lab prior to administration of ditions are known to be associated with Cancer Center) discussed the outcomes therapy. an increased risk of lymphoma, but their of a study designed to identify the drivers impact on disease progression is less clear. of ibrutinib resistance in MCL. Through MCL Outcomes Research In this study, researchers analyzed data Moderator: Bijal Shah, MD, H.Lee Moffitt analysis of several resistant cell lines and from a “natural history” study designed to Cancer Center patient samples, researchers determined track variables that may influence disease Clinicians reported several population- that there is no single or set of drivers. to uncover any relationship between auto- level analyses that together strengthen Rather, resistance arises from a large-scale understanding of how individual patient immune diseases and MCL. Data showed remodeling of the cellular networks that characteristics impact MCL treatment that MCL patients with a history of B-cell- then lead to aggressive proliferation of outcomes. mediated autoimmune disease, primarily MCL. This type of mechanism presents rheumatoid arthritis, showed inferior over- Thomas Habermann, MD (Mayo Clinic) significant challenges for developing all and event free survival. These results reported on studies evaluating the impact individual inhibitor treatments; however, highlight the need for additional studies to of the time from MCL diagnosis to treat- targeting the process of remodeling itself better understand the nature of the impact ment initiation (DTI) on disease outcomes. by preventing the global increase in gene of these comparatively common autoim- The study included 271 patients and expression that precedes the development mune diseases on MCL natural history so assessed event free survival (EFS), progres- of resistance has the potential to slow or that unique elements of disease manage- sion, initiation of another lymphoma ther- prevent resistance. Work is currently under- ment for these patients may be defined. apy, or death from any cause. The study way to identify early markers of resistance found that a short DTI is strongly associat- Max Goldman, BA (Emory University) that can be targeted before the required ed with poor outcomes and that patients examined the practice of surveillance remodeling occurs. with longer DTI have less aggressive clin- imaging in MCL. During remission, the Bijal Shah, MD, (H. Lee Moffitt Cancer ical characteristics and better outcomes. patient is most often placed under “surveil- Center) reported on the use of cell-based Importantly, this pattern persists regard- [CONTINUED NEXT PAGE]

lymphoma.org 11 MCL WORKSHOP - BIOMARKERS

Krithika Shanmugasundaram, MD (Emory investigators with clinical, translational, or MCL Workshop University) discussed the impact of ther- survivorship questions. [CONTINUED FROM PAGE 11] apy intensity on survival for MCL patients lance” and is periodically evaluated using MCL Prognostic and Predictive deferring therapy. While there are data CT or PET scan to detect relapse. To better Biomarkers showing that patients may safely defer understand if there is a role for surveillance Moderator: Brad Kahl, MD, Washington therapy for indolent disease, there is little imaging in MCL, 801 images for patients in University Medical School in Saint Louis information surrounding the intensity of In a series of presentations on prognostic their first remission were collected; of these therapy once it is initiated. In the work pre- and predictive biomarkers, clinical scien- images, only 3.5 percent led to a diagnosis sented by Dr. Shanmugasundaram, out- tists provided updates on new approach- of relapse. This outcome is consistent with comes for patients who received intensive es to the collection and analysis of the clinical observation that most relapses patient samples to more accurately strati- therapy (high-dose cytarabine as part of are diagnosed when the patient presents fy patients and predict clinical response. induction regimen or autologous stem cell with clinical symptoms. This rate of detec- transplantation in first complete or partial Hilka Rauert-Wunderlich, Dr. rer. nat. tion is similar for both PET and CT scan, and remission) were compared to outcomes for (University of Wuerzburg) discussed results each modality produced a large number patients who received less intense therapy. from a study exploring the utility of the of false positives. This study in MCL mirrors This comparison revealed no significant MCL35 nanostring assay for stratifying the findings for all non-Hodgkin lympho- difference in overall or progression free MCL patients into low-, standard-, and mas, demonstrating that surveillance survival based on the intensity of therapy. high-risk groups. In a study of 169 MCL imaging does not confer a significant sur- These findings indicate that less intensive patients from the European Mantle Cell vival benefit to patients. The findings from therapy may be appropriate in patients Lymphoma Network, a set of 35 “prolif- this study support the most conservative who have deferred treatment for their eration signature” genes was analyzed application of surveillance imaging, as disease. for each patient and the results were there is no significant survival benefit and compared to patient prognosis that was imaging is associated with high emotional Jonathon Cohen, MD (Emory University) generated from two other validated tools, and financial burden as well as unneces- presented findings from the first report the Mantle Cell Lymphoma International sary exposure to radiation. of the Lymphoma Epidemiology of Prognostic Index (MIPI) and Ki-67 prolifer- Outcomes (LEO) Cohort, an observational Andrew Ip, MD (Emory University) dis- ation rate. Researchers found that while cohort study that includes eight academic cussed the impact of comorbidities on the MCL35 assay provided a prognosis that sites throughout the United States. 270 the outcome of autologous stem cell was in agreement with other established MCL patients enrolled between 2015 and transplant (ASCT). Though the validat- measures, it also provided additional 2018 are included in this report. For each ed Hematopoietic Cell Transplantation information that permitted stratification of patient, data on tissue samples at baseline Comorbidity Index (HCT-CI) for lymphoma patients. Stratification is not only import- and treatment, treatment received, and indicates that ASCT is appropriate for many ant for better understanding prognosis, outcomes were collected. Analysis of col- fit patients under 60, the recent emergence but for informing the organization of clin- lected data reveals heterogeneity in MCL [CONTINUED NEXT PAGE] of new therapies for this patient group rais- presentation and es the question of whether the impact of management in comorbidities on ASCT outcomes in MCL the United States, remains the same. Researchers analyzed highlighting a data from Emory Winship Cancer Institute need for strati- from MCL patients who received ASCT fication criteria from 2010–2017. Findings indicate that to support first- consistent with earlier recommendations, line treatment when managed appropriately, comorbid- selection. Strong ities should not be a barrier to ASCT. One study accrual is potential exception is obesity, which was continuing, and associated with inferior survival indicat- this resource ing that additional interventions may be can be utilized appropriate for these patients. by interested Depiction of the RNA scope process described in Dr. Quintanilla-Fend’s presentation. Illustration courtesy Leticia Quintanilla-Fend, MD, University of Tuebingen.

12 Research Report MCL WORKSHOP - BIOMARKERS MCL WORKSHOP - CLINICAL TRIALS

ical trials that assess treatment efficacy for samples, where the current proliferation from a phase I/IB study on ibrutinib and patients with different risk levels. signature used to determine MCL prognosis buparlisib combination therapy in MCL. In is not effective. Development of this assay this study, two doses of ibrutinib within the Leticia Quintanilla-Fend, MD (University not only improves understanding of disease context of combination therapy were test- of Tuebingen) presented a study aimed at subtypes and their prognosis, but can differ- ed to determine safety and efficacy. When better understanding the prognostic role entiate between subtypes in the setting of two drugs are given in combination, it is of the gene SOX11 in MCL. While SOX11 a clinical trial where different subtypes may important to ensure that the any additive expression in MCL is important for the iden- respond differently to treatment. side effects are controlled and that there tification of important subsets of MCL in the is no synergistic activity that makes the clinic, how it is related to disease prognosis Anita Kumar, MD (Memorial Sloan Kettering combination unsafe. In addition, the most is controversial. Perhaps one explanation for Cancer Center) discussed methods for effective and best-tolerated dose must be the controversy is that methods to measure assessing minimal residual disease (MRD) determined. Here, 15 patients were evalu- its level in MCL cells are not quantitative, in patients who have received combined ated for response to the combination; elev- and thus do not provide specific informa- immunotherapy and ASCT. Currently, MRD en patients achieved complete response tion about protein levels. Rather, current measured using a test called allele-specific (CR) and four patients achieved a partial methods are restricted to simply indicating oligonucleotide polymerase chain reaction response, indicating that the combination the presence or absence of the protein. In (ASO-PCR) is a strong predictor of relapse, of ibrutinib and buparlisib holds promise for this study, researchers worked to establish but this test is patient-specific, takes time, MCL treatment. a more sensitive test via the RNAscope pro- and requires a specialized laboratory. cess so that SOX11 levels can be measured Technologies that test for the presence of Anita Kumar, MD (Memorial Sloan Kettering in tissue sections. Using this test, researchers MRD using deep-sequencing of the B-cell Cancer Center) presented preliminary results found that SOX11 expression is variable in receptor DNA that is circulating in the blood from a trial evaluating the use of lenalido- MCL, an indicator that levels may be asso- may be potentially more sensitive and mide in combination with cytotoxic induc- ciated with different behavior in malignant easier to implement in the clinical setting. tion chemotherapy followed by rituximab cells. Having developed a reliable test to This study evaluated the performance of and lenalidomide maintenance in the initial differentiate levels of SOX11 expression, this DNA-sequencing based MRD assay in a treatment of MCL. Of the 20 patients who researchers are now able to better evaluate group of uniformly treated MCL patients. A have completed treatment, 95 percent are the role of this protein in disease and deter- total of 166 patient samples were analyzed PET-negative and have achieved a complete mine if it is a reliable prognostic marker. using the assay to predict clinical relapse remission. After a median follow-up of 15 in MCL and found that detection of DNA in months, 18 have evidence of ongoing remis- Elias Campo MD, PhD (Hospital Clinic de lymphocytes and/or circulating in the blood sion. Early results of this study indicate that Barcelona) reported on the development was found to be predictive of relapse. The lenalidomide and sequential chemotherapy of a molecular test to more reliably identify MRD test was more sensitive using DNA followed by lenalidomide and rituximab both conventional MCL (cMCL) and the from inside circulating cells versus cell-free maintenance is a promising therapy for MCL. clinical and biological subtype Leukemic DNA circulating in the blood, likely due to Data analysis from this study is ongoing. non-nodal MCL (nnMCL). Currently, there is the fact that MCL commonly has circulating a lack of clinical tools that recognize these lymphocytes in the blood. Continued vali- Manali Kamdar, MD, MBBS (University of two subtypes and little information about dation of this method may lead to its use for Colorado) provided an update of results genetic drivers of progression and out- less invasive patient monitoring. from a study comparing bendamustine-rit- comes. In this study, researchers developed uximab (BR) to R-HyperCVAD/MTX/ARAC and validated a 16-gene assay to differenti- MCL Clinical Trials (RH) prior to ASCT. Initial results showed that ate between cMCL and nnMCL. Sequential Moderator: Martin Dreyling, MD, PhD, comparable response rates and MRD nega- samples taken from patients over the course University Hospital LMU Munich tivity could be achieved by either treatment In a series of presentations on outcomes of disease were evaluated and the assay regimen, though RH exhibited more toxicity of recent clinical trials, researchers shared was found to make prognostic evaluation promising results from early-phase stud- and inadequate stem cell mobilization, a achievable with more robust genetic anal- ies and discussed how findings may even- feature that makes RH less desirable before ysis of known genetic alterations (such as tually inform treatment algorithms. transplant. This updated analysis includes TP53 and CDKN2A); with further study, this 4.8 years of follow-up data, and showed a Connie Batlevi, MD, PhD (Memorial Sloan may aid in treatment decisions. This assay five-year overall survival rate of 79 percent Kettering Cancer Center) discussed results is especially useful in evaluating leukemic [CONTINUED NEXT PAGE]

lymphoma.org 13 MCL WORKSHOP - CLINICAL TRIALS

MCL Workshop evaluates bortezomib efficacy when used In ongoing trials, a large-scale study evalu- during BR induction, the efficacy of lena- ates the benefit of ibrutinib in addition to [CONTINUED FROM PAGE 13] lidomide during rituximab maintenance, or in place of autologous transplantation for BR and 81 percent for RH. These data and provides additional data on genes, in younger patients. The trial has accrued indicate that BR is an excellent backbone methylation patterns, and gene expression over 200 patients across twelve European for induction therapy in transplant eligible profiles that impact disease response to countries. In patients over 60 years old, patients and needs to be explored further treatment and progression. Dr. Kahl also the MCL ELDERLY R2 trial compares an in larger phase III trials. noted three additional studies under- alternating induction R-CHOP/R-HAD to Brad Kahl, MD (Washington University way in this population, the SHINE trial, R-CHOP only. Patients who respond to Medical School in Saint Louis) continued Acerta trial, and PrE0404 in relapsed and either treatment will then receive either the discussion of induction therapy before refractory patients. For younger patients, combined rituximab-lenalidomide main- transplant by discussing results from a trials are currently underway comparing tenance or rituximab only for two years. pilot study evaluating the performance of autologous hematopoietic stem cell This study has recruited more than 400 BR when it replaces R-CHOP in an estab- transplantation followed by rituximab patients and is active in seven European lished treatment regimen that includes maintenance with rituximab maintenance countries. In addition, two other trials alternating cycles of R-MaxiCHOP with alone in MRD-negative patients during in elderly patients are evaluating new R-high-dose cytarabine (HiDAC-R). The first complete remission (EA4151) and a treatment combinations. Future trials will rationale for this replacement is that BR trial comparing 3 different induction strat- evaluate non-chemotherapy approaches appears to be superior to R-CHOP in MCL. egies prior to transplantation (EA4181). In in first line of elderly patients. addition, PrE0405 assesses the utility of BR This study evaluates whether alternating Summary cycles of BR and HiDAC-R outperform the plus venetoclax in the relapsed refractory For over a decade, the Lymphoma established regimen in patients eligible setting. Together, these trials hold promise Research Foundation MCL Consortium has for transplant. Researchers evaluated stem for determining which treatments are served as a resource for MCL investigators cell mobilization and response to treat- most effective for specific patient groups, through research funding, providing a ment. The BR and HiDAC-R regimen exhib- improving overall outcomes for patients platform for the exchange of scientific ited effective mobilization and resulted in with MCL. ideas to accelerate innovation in MCL, and a complete response rate of 79 percent, an Martin Dreyling, MD, (University Hospital promoting collaborations that increase improvement over the 54 percent report- LMU Munich) spoke about current gener- the impact of individual research efforts. ed for the R-MaxiCHOP and HiDAC-R regi- ation of European MCL Network Studies. The progress in MCL is both significant and men. This study provides additional insight In the past two years, progress has been ongoing, with the continuing develop- into the optimal treatment regimen for made on several fronts. A recent MCL ment of novel therapies and the introduc- MCL before transplant and provides a trial in younger patients showed that the tion of new methodologies for monitoring “backbone” with which other novel thera- addition of high-dose cytarabine (ARA-C) and understanding patients’ response to pies may be used to achieve better results to R-CHOP results in superior response treatment. Research into the biology of for patients. to therapy. The completed French LyMa MCL and mechanisms of malignancy and Update on International Clinical trial showed that rituximab following resistance has revealed new avenues for Research Efforts in MCL transplant further improves survival. novel therapies. The Lymphoma Research To conclude the meeting, two leading Additionally, rituximab maintenance also Foundation looks forward to continuing MCL investigators, both members of the demonstrated an improvement in survival to play a central role in programs aimed MCLC Executive Committee, provided in elderly patients. Finally, current treat- at improving treatment and outcomes for updates on planned MCL trials. Brad Kahl, ment guidelines issued by the European MCL patients. MD, spoke about five National Clinical Society for Medical Oncology (ESMO) The Foundation extends special thanks to Trials Network (NCTN) initiatives that recommend both ibrutinib and lenalid- AstraZeneca Pharmaceuticals and Celgene mirror those carried out by the European omide-rituximab as first-choice targeted Corporation for supporting the MCL MCL consortium aimed at optimizing therapies in relapsed MCL. Together, these Scientific Workshop through unrestricted treatment approach specifically for older/ examples illustrate that optimization of educational grants. less fit patients, younger/fit patients and current therapy and utilization of newer relapsed/refractory disease. In particular, therapies in the treatment of MCL contin- for the older/less fit population, E1141 ues to improve patient care.

14 Research Report SCIENTIFIC ADVISORY BOARD

The Lymphoma Research Foundation’s volunteer Scientific Advisory Board, comprised of 45 world-renowned lymphoma experts, guides the Foundation’s research activities, seeking out the most innovative and promising lymphoma research projects for support.

Thomas M. Habermann, MD Jonathan W. Friedberg, MD, MMSc Kanti R. Rai, MD, BS Chair James P. Wilmot Cancer Institute Hofstra Northwell School of Medicine Mayo Clinic, Rochester University of Rochester Medical Center Kerry Savage, MD Andrew D. Zelenetz, MD, PhD Leo I. Gordon, MD, FACP British Columbia Cancer Agency Chair-Elect Immediate Past Chair Memorial Sloan Kettering Cancer Center Robert H. Lurie Comprehensive Cancer Center Laurie Sehn, MD, MPH of Northwestern University British Columbia Cancer Agency Ranjana Advani, MD Stanford University School of Medicine Steven M. Horwitz, MD Margaret Shipp, MD Memorial Sloan Kettering Cancer Center Dana-Farber Cancer Institute Ash Alizadeh, MD, PhD Stanford University School of Medicine Eric D. Hsi, MD Sonali M. Smith, MD Cleveland Clinic The University of Chicago Stephen Ansell, MD, PhD Mayo Clinic, Rochester Brad S. Kahl, MD Eduardo M. Sotomayor, MD Washington University Medical School George Washington University Nancy Bartlett, MD GW Cancer Center Washington University Medical School Kara Kelly, MD Oishei Childrens Hospital Christian Steidl, MD Kristie A. Blum, MD University of Buffalo Jacobs School of Medicine British Columbia Cancer Agency Winship Cancer Institute of Emory University and Biomedical Sciences John Timmerman, MD Catherine Bollard, MD, MBChB Ann S. LaCasce, MD University of California, Los Angeles, Children’s National Medical Center Harvard Medical School Jonsson Comprehensive Cancer Center George Washington University Dana-Farber Cancer Institute Sven de Vos, MD, PhD Ethel Cesarman, MD, PhD Brian K. Link, MD University of California, Los Angeles, New York-Presbyterian Hospital University of Iowa Jonsson Comprehensive Cancer Center Weill Cornell Medicine John P. Leonard, MD David Weinstock, MD Bruce D. Cheson, MD, FACP, FAAAS, FASCO Past Chair, 2012-2015 Dana-Farber Cancer Institute Past Chair, 2010-2012 New York-Presbyterian Hospital Hans-Guido Wendel, MD Georgetown University Hospital Weill Cornell Medicine Lombardi Comprehensive Cancer Center Memorial Sloan Kettering Cancer Center Izidore S. Lossos, MD Morton Coleman, MD Michael E. Williams, MD, ScM University of Miami Health System University of Virginia Cancer Center New York-Presbyterian Hospital Sylvester Comprehensive Cancer Center Weill Cornell Medicine Thomas Witzig, MD Ari Melnick, MD Mayo Clinic, Rochester Sandeep Dave, MD, MS New York-Presbyterian Hospital Duke University Weill Cornell Medicine Anas Younes, MD Memorial Sloan Kettering Cancer Center Kieron M. Dunleavy, MD Lindsay Morton, PhD George Washington University National Cancer Institute GW Cancer Center Owen O’Connor, MD, PhD Members Emeritus Kojo S.J. Elenitoba-Johnson, MD Columbia University Medical Center Raymond and Ruth Perelman School of Medicine Joseph R. Bertino, MD University of Pennsylvania Laura Pasqualucci, MD Founding Chair Columbia University Rutgers Robert Wood Johnson Medical School Andrew M. Evens, DO, MSc Herbert Irving Comprehensive Cancer Center The Cancer Institute of New Jersey Rutgers Cancer Institute Charles Coltman, MD Christopher R. Flowers, MD, MS Barbara Pro, MD San Antonio Cancer Institute Winship Cancer Institute of Emory University Robert H. Lurie Comprehensive Cancer Center of Northwestern University Saul Rosenberg, MD Stanford University School of Medicine

About the Research Report Double Your Impact for MCL Research Research Report is a publication of LRF is proud to be the nation’s largest private funder of the Lymphoma Research Foundation, mantle cell lymphoma (MCL) research. Now you have the National Headquarters providing the latest updates on our chance to double your impact through a special donor grantees and their progress, as well Wall Street Plaza challenge gift. as on the work of the Foundation. 88 Pine Street, Suite 2400 This gift, given by her husband, honors the life of Marcia The Lymphoma Research Foundation New York, NY 10005 Greene, who passed away in 2017. Her life was extended is the nation’s largest non-profit (212) 349-2910 by more than eight years because of the generosity of organization devoted to funding earlier donors to MCL research. Through September 14, Helpline: (800) 500-9976 innovative lymphoma research and 2018, this gift will match other gifts for MCL research [email protected] serving the lymphoma community dollar for dollar, up to $56,000. Website: lymphoma.org through a comprehensive series Email: [email protected] of education programs, outreach This is a great opportunity for donors to double their initiatives, and patient services. gifts and continue to fund research so that everyone dealing with an MCL diagnosis can have a brighter future. For more information, or to donate, visit support.lymphoma.org/mclmatch. © 2018 Lymphoma Research Foundation

lymphoma.org 15 NONPROFIT ORGANIZATION US POSTAGE PAID Lymphoma Research Foundation NEW YORK, NY Wall Street Plaza PERMIT #370 88 Pine Street, Suite 2400 New York, NY 10005

IN THIS ISSUE: 2018 ANNUAL GALA 2018 MCL Scientific Workshop 1 THURSDAY, SEPTEMBER 27 MCL Biology 2 Keynote 8 The Plaza ● New York City Novel Pathways and Targets 9 Personalization of Therapy 10 HONORING Outcomes Research 11 John P. Leonard, MD Seattle Genetics Biomarkers 12 Clinical Trials 13 Distinguished Service Award Corporate Leadership Award

Features: CHAIRED BY Letter from the CEO 2 Laura & Lloyd Blankfein MCL, LCRMP Grants Announced 3 Scientific Advisory Board 15

t Scan using your smartphone to read our Research Reports online.

New LRF Grantees The Foundation announces 2018 grants in MCL and the participants lymphoma.org/gala in its Lymphoma Clinical Research Mentoring Program. For more information contact Taylor Zitay Kahn, Director of Distinguished Events, Visit page 3 for details. [email protected] or 646 465-9103 16 Research Report