Perspective Open Access The EHA Research Roadmap: Malignant Lymphoid Diseases Martin Dreyling1, Marc André2, Nicola Gökbuget3, Hervé Tilly4, Mats Jerkeman5, John Gribben6, Andrés Ferreri7, Pierre Morel8, Stephan Stilgenbauer9, Christopher Fox10, José Maria Ribera11, Sonja Zweegman12, Igor Aurer13, Csaba Bödör14, Birgit Burkhardt15, Christian Buske16, Maria Dollores Caballero17–19, Elias Campo20, Bjoern Chapuy21,22, Andrew Davies23, Laurence de Leval24, Jeanette Doorduijn25, Massimo Federico26, Philippe Gaulard27, Francesca Gay28, Paolo Ghia29, Kirsten Grønbæk30,31, Hartmut Goldschmidt32, Marie-Jose Kersten33, Barbara Kiesewetter34, Judith Landman-Parker35, Steven Le Gouill36, Georg Lenz37, Sirpa Leppä38, Armando Lopez-Guillermo39, Elizabeth Macintyre40, Maria Victoria Mateos Mantega41, Philippe Moreau42, Carol Moreno43, Bertrand Nadel44, Jessica Okosun45, Roger Owen46, Sarka Pospisilova47, Christiane Pott48, Tadeusz Robak49, Michelle Spina50, Kostas Stamatopoulos51, Jan Stary52, Karin Tarte53, Allessandra Tedeschi54, Catherine Thieblemont55, Ralf Ulrich Trappe56, Lorenz H. Trümper57, Gilles Salles58 Correspondence: Martin Dreyling (Martin.Dreyling@med.uni-muenchen.de). In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coor- dinated by 1 to 2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell- based Immune Therapies; and Gene Therapy. 1 Department of Medicine III, LMU Hospital, Munich, Germany 18 Department of Medicine at the University of Salamanca, Spain 2 Université Catholique de Louvain, CHU UcL Namur, Yvoir, Belgium 19 El Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, 3 Department of Medicine II, Hematology/Oncology, University Hospital Frankfurt, Spain Goethe University, Frankfurt, Germany 20 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 4 INSERM U1245, Department of Hematology, Centre Henri Becquerel and Spain Université de Rouen, France 21 Department of Hematology, Oncology and Tumor Immunology, Charité, 5 Skåne University and Lund University, Lund, Sweden University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany 6 Barts Cancer Institute, Queen Mary University of London, United Kingdom 22 Berlin Institute of Health, Berlin, Germany 7 Lymphoma Unit, Department of Onco-hematology, IRCCS San Raffaele Scientific 23 Southampton NCRI/UK Experimental Cancer Medicines Centre, Faculty of Institute, Milano, Italy Medicine, University of Southampton, United Kingdom 8 Service Hematologie Clinique Therapie Cellulaire, CHU Amiens Picardie, Amiens, 24 Department of Laboratory Medicine and Pathology, Institute of Pathology, France Lausanne University Hospital and Lausanne University, Lausanne, Switzerland 9 Comprehensive Cancer Center Ulm (CCCU), Sektion CLL Klinik für Innere 25 Department of Hematology, Erasmus MC Cancer Institute, University Medical Medizin III, Universität Ulm, Germany Center Rotterdam, Rotterdam, the Netherlands 10 School of Medicine, University of Nottingham, United Kingdom 26 Città di Lecce Hospital, GVM Care & Research, Lecce, Italy 11 Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep 27 Département de Pathologie, Hôpital Henri Mondor, AP-HP, Créteil, France Carreras Research Institute, Badalona, Spain 28 Clinical Trial Unit, Division of Hematology 1, AOU Città Della Salute e Della 12 Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Scienza, University of Torino, Italy the Netherlands 29 Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, 13 University Hospital Centre Zagreb and Medical School, University of Zagreb, Italy Croatia 30 Department of Hematology, Rigshospitalet, Copenhagen, Denmark 14 HCEMM-SE Molecular Oncohematology Research Group, Department of 31 Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Denmark Hungary 32 University Hospital Heidelberg, Internal Medicine V and National Center for 15 Experimentelle und Translationale päd. Hämatologie u Onkologie, Leitung der Tumor Diseases (NCT), Heidelberg, Germany Bereiche Lymphome und Stammzelltransplantation, Universitätsklinikum Münster 33 Department of Hematology, Amsterdam UMC, University of Amsterdam, Cancer (UKM), Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Center Amsterdam and LYMMCARE, Amsterdam, the Netherlands Onkologie, Munich, Germany 34 Department of Medicine I, Division of Oncology, Medical University of Vienna, 16 Institute of Experimental Cancer Research, CCC Ulm, University Hospital Ulm, Austria Germany 35 Pediatric Hematology Oncology, Sorbonne Université APHP/hôpital A 17 Clinical and Transplant Unit, University Hospital of Salamanca, Spain Trousseau, Paris, France 1 Dreyling et al Research Roadmap: Malignant Lymphoid Diseases M alignant lymphoid diseases represent the most fre- This is true for the most aggressive malignancies (eg, ALLs, quent hematologic malignancies, with an age-ad- T-cell lymphomas, and some forms of DLBCL), which still are justed estimated incidence of 24.5 per 100,000 frequently fatal. In addition, the lack of cure in patients with inhabitants in Europe,2 and are associated with multiple myeloma or indolent lymphoma is equally challenging. significant mortality3 and morbidity. This disease group is Furthermore, short- or long-term morbidities such as infertility, highly heterogeneous in terms of frequency, epidemiology, biol- secondary malignancies, as well as cardiac, pulmonary, renal, ogy, genetic abnormalities, and outcome. Although in a way all or neurological dysfunction are associated with intensive treat- individual lymphoma subtypes may be characterized as rare dis- ment in HL or DLBCL. Chronic exposure to therapeutic agents eases, some of them are relatively common, for example, multi- such as in indolent lymphoma and CLL also represents a health ple myeloma, chronic lymphocytic leukemia (CLL), diffuse large burden for patients, as well as an increasingly relevant economic B-cell lymphomas (DLBCLs), follicular lymphomas (FLs), and burden for the European Union.14,15 Attention to malignancies Hodgkin lymphomas (HLs). Others are less common, for exam- occurring in elderly patients should also be considered in this ple, mantle cell lymphoma (MCL), acute lymphoblastic leukemia regard given the fact that life expectancies continue to grow. (ALL), T-cell lymphoma, and mucosa-associated lymphoid tis- European co-operative groups have been leading clinical sue (MALT) lymphoma, Waldenstrom’s Macroglobulinemia, or research in lymphoid malignancies in the past decades. Progress even very rare, for example, some subsets of marginal zone lym- is being made in investigating the role of targeted agents in phomas (MZLs) and HIV-associated lymphoma. After the prog- well-characterized molecular subsets. The number of new ther- ress made in the morphological classification of these tumors in apeutic agents under development in this field demands further the 1990s, the advent of large-scale genomic approaches enabled academic research collaboration. For example, analyzing the identification of multiple molecular subsets, which may further medico-economic impacts of patient management should clar- subdivide the different entities in multiple rare diseases.4–6 These ify the costs and benefits of novel therapeutic strategies, includ- achievements justify the need for European-based epidemiolog- ing those related to public health economics. These groups also ical studies and contributions to the InterLymph consortium7 need further support in their translational research activities, to investigate the role of environmental and lifestyle factors, especially in their efforts to constitute and analyze large bio- which, in the context of inherited genetic background, may banks with high-quality clinical annotations. Efforts should favor the development of these malignancies. also aim to eliminate the different outcomes observed in dif- Significant progress was also made in unraveling key biologi- ferent parts of Europe and to improve patients’ survival and cal features of these diseases, including (1) the more precise delin- quality of life. eation of intrinsic genetic defects in tumor cells, delineation still ongoing with next-generation sequencing (NGS) approaches6,8,9; (2) the growing understanding of the complex interplays between HODGKIN LYMPHOMA malignant cells and their microenvironment, which is especially Introduction critical in these diseases arising in lymphoid organs10; and (3) Classical HL is a highly curable disease and for both localized the emerging identification of constitutional genetic traits associ- and advanced-stage diseases, >90% of patients are alive 5 years ated with an increased susceptibility to develop these malignan- after diagnosis. During their follow-up, however, a significant cies.11,12 Although several European groups have already made proportion of these young patients experience serious long-term outstanding contributions to this field, in part within large inter- toxicities related to the treatments of lymphoma. The reduction national consortia, further achievements will only be possible of long-term, treatment-related toxicities remains the goal of if major investments can be realized. These should particularly actual clinical trials. focus on establishing new cellular and animal models which are critically rare in the field of mature lymphoid malignancies to European research contributions better understand how these diseases develop and for preclinical Based on the seminal work of Gallamini et al,16 it appears that assessment of new therapeutic agents. an early PET scan (e-PET) performed after 2–3 cycles of ABVD Despite important advances in the past few years,13 the survival was able to segregate patients into two categories; early PET of patients with lymphoid malignancies remains unsatisfactory. negative patients with an excellent prognosis and a possibility to 36 Service d’Hématologie, Clinique du Centre Hospitalier Universitaire (CHU) de 50 Division of Medical Oncology and Immune-related Tumors, National Cancer Nantes, France Institute, Aviano, Italy 37 Medical Department A for Hematology, Oncology and Pneumology, University 51 Institute of Applied Biosciences, Centre for Research and Technology Hellas, Hospital Münster, Germany Thessaloniki, Greece 38 University of Helsinki and Helsinki University Hospital Comprehensive Cancer 52 Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine, Centre, Helsinki, Finland Charles University Prague University Hospital, Prague, Czech Republic 39 Department of Hematology, Hospital Clínic de Barcelona, Spain 53 Immunology and Cell Therapy Lab at Rennes University Hospital, Rennes, 40 Onco-hematology, Université de Paris and Necker-Enfants Malades Hospital, France Assistance Publique-Hôpitaux de Paris, France 54 Department of Hematology, Niguarda Hospital Milano, Italy 41 Complejo Asistencial Universitario de Salamanca, IBSAL, CIC, Universidad de 55 Department of Hemato-Oncology, Saint-Louis Hospital, Assistance Publique- Salamanca, Ciberonc, Salamanca, Spain Hôpitaux de Paris (AP-HP), Paris, France 42 Hematology Department, University Hospital Hotel-Dieu, Nantes, France 56 Department of Internal Medicine II: Haematology and Oncology, DIAKO Hospital 43 Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona, Spain Bremen, Germany 44 Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France 57 Hematology and Medical Oncology, University Medicine Goettingen, Germany 45 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of 58 Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer London, United Kingdom Center, Weill Cornell Medicine, New York, NY, USA 46 St James’s Institute of Oncology, Leeds, United Kingdom Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on 47 Department of Internal Medicine—Hematology and Oncology and Department behalf of the European Hematology Association. This is an open access article of Medical Genetics and Genomics, Faculty of Medicine, Masaryk University and distributed under the Creative Commons Attribution License 4.0 (CCBY), which University Hospital Brno, Czech Republic permits unrestricted use, distribution, and reproduction in any medium, provided 48 Klinisch-experimentelle Hämatologie, Medizinische Klinik II, Hämatologie und the original work is properly cited. Internistische Onkologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, HemaSphere (2022) 6:6(e726). Germany http://dx.doi.org/10.1097/HS9.0000000000000726. 49 Medical University of Lodz, Poland Received: March 17, 2022 / Accepted: April 21, 2022 2 (2022) 6:6 www.hemaspherejournal.com reduce the amount of treatment; and early PET-positive patients ACUTE LYMPHOBLASTIC LEUKEMIA with a worse prognosis suggesting no reduction but possibly Introduction intensification of treatment. Acute lymphoblastic leukemia is a life-threatening disease In early stage HL, three European studies based on this affecting children and adults. Treatment consists of combina- approach were performed and published in the last 5 years.17–19 tion chemotherapy, with allogeneic hematopoietic stem cell In early stage favorable HL, the objective was to avoid radio- transplantation (HSCT) restricted to high-risk or relapsed ALL. therapy in e-PET negative patients. All three trials were not able Five-year event-free survival is correlated to age and in contem- to demonstrate the noninferiority of the no radiotherapy arm in porary treatment, protocols reach over 80% for children and terms of progression-free survival (PFS), but the overall survival 40%–70% for adults, due to the increased incidence of poor (OS) was excellent and did not show any difference. Omission prognostic features and lower tolerability of intensive chemo- of radiotherapy is at the price of some reduction in tumor con- therapy in older patients.1 trol and should be balanced with the expected individual risk associated with radiotherapy. European research contributions In early stage intermediate/unfavorable disease, the same The treatment of ALL in Europe is undertaken by national strategy was applied.18,20 In the HD17 study, noninferiority of study groups and international consortia such as BFM/AEIOP the no radiotherapy arm was demonstrated and in the H10 and ALL-Together for children and EWALL for adults. study a 2.5% of difference of PFS was observed between the 2 National study group clinical databases, reference laborato- arms suggesting that radiotherapy can be omitted in this situa- ries, or associated biobanks are essential for research on dis- tion. For e-PET-positive patients, only the H10 study evaluated ease biology and prognostication and are sources of reliable early intensification of chemotherapy and demonstrated a better real-world data. European standardization for monitoring of PFS with this strategy; improvement of OS was of borderline minimal residual disease (MRD) by the EuroMRD/ESLHO significance. group made risk-based individual treatment modification pos- In advanced-stage HL, three randomized studies evaluated sible. As a basis for intergroup trials, consensus definitions for reduction of the amount of treatment based on an e-PET eval- adverse events and treatment response have been developed uation.21–23 All these three studies were successful and demon- for pediatric ALL.27,28 Gene expression profiling and sequenc- strated that a reduction of the amount of treatment given is ing have identified many new subtypes of B-cell precursor possible when an e-PET negativity is reached after 2 cycles (BCP) and T-cell lineage ALL; their number has complicated of chemotherapy. For e-PET negative patients, omission of both European standardization and risk-based personalized Bleomycin, reduction to 4 cycles of escBEACOPP, or de-escala- therapy. tion to ABVD were validated by these three trials. Immune therapies with bispecific antibodies and conjugated In adolescents and young adults (AYA), to limit gonadal dam- antibodies for BCP-ALL have replaced standard of care chemo- age and second malignancies, the European trial EuroNet PHL therapy in R/R ALL,29 led for the first time to marketing autho- C124 lead to the replacement of procarbazine with dacarbazine rization for MRD-positive ALL30 and are increasingly being and to restriction of RT indications to patients with an adequate tested in first-line trials. CAR-T cell products became available response after 2 first cycles of OEPA. EuroNet PHL C2 explores within clinical trials and with the marketed product for patients moderate treatment intensification in order to further limit RT younger than 25 years. Further trials are directed to the clinical indications. evaluation of inhibitors directed to BCR-ABL-like or JAK-class Finally, the incorporation of Brentuximab Vedotin (BV) fusion-gene subgroups.31 On the other hand, the clinical impact and checkpoint inhibitors in the ABVD regimen was evalu- of intensive conventional treatments like HSCT with TBI-based ated recently. Two European studies25,26 showed that replacing conditioning has been underlined.32 Bleomycin by one of these two drugs could be achieved safely. BV-AVD increased e-PET negativity compared with ABVD. Proposed research for the Roadmap Evaluation of the prognostic impact of the myriad oncogenic Proposed research for the Roadmap subgroups in modern, MRD-risk stratified, treatment proto- Individualization of treatment should be pursued in the con- cols is challenging. It is essential, in addition to identifying and text of PET-adapted therapy. Besides early PET negativity, total unraveling potential prognostic lesions, to increasingly focus on metabolic tumor volume appears to be an important prognostic functional studies addressing tumor dependency of new lesions factor and should be tested for better tailoring the risk-adapted (including those found in subclones) in relevant models. In vitro treatment strategy. testing strategies to select compounds for individual refractory Another possible important avenue for future research is the patients are emerging33 and require European concertation and detection of tumor DNA in the blood of the patients. Its poten- adaptation of data management, clinical trial design, and drug tial use to identify some baseline prognostic factors, monitor treat- accessibility circuits. Epigenetic landscapes are more accessible ment, and detect early relapses warrant future development. In this for the identification of actionable targets, such as hypomethyl- context, systematic banking of tumor and plasma samples, such ating agents34 and multiparameter prognostic scores will increas- as PET images is recommended in future European trials. BV and ingly combine clinical and molecular features.35 Our knowledge checkpoints inhibitors have a definitive place in refractory/relapsed about the supportive (and protective) role of the bone marrow HL lymphoma, their possible integration into first line for selected microenvironment should also be expanded.1 It is also essential patients need still to be demonstrated in future phase III trials. to address future ALL classification, which needs to integrate molecular oncogenic characteristics and next-generation MRD Anticipated impact of the research and requires standardization of the optimal diagnostic standards. Reducing toxicities and possibly improving the high-cure rate Late effects of treatment, such as osteonecrosis,36 are increas- will remain the goal of our future strategies and probably led to ingly relevant with improved ALL survival, requiring joint even more individualized therapy, incorporating PET, cell-free efforts of pediatric and adult study groups to better understand DNA, and possibly new drugs. As the costs of these new tools biology, improve surveillance and define potential treatment are elevated, they will probably not apply to each patient and modifications. Age is one of the most important prognostic be restricted to a subset of HL. Special attention should be given factors for ALL. Uncertainty persists on which types of pedi- to the dissemination of these expensive innovations (and future atric-based therapies are tolerated in different age groups so, at ones such as CART-T cells) in all countries in Europe. least, clear reporting standards are necessary. The development 3 Dreyling et al Research Roadmap: Malignant Lymphoid Diseases of innovative treatment strategies for older patients can help different treatment approaches.43,44 Additionally, European hema- younger patients and vice versa. tologists participated in major clinical trials aiming at improving Increasing regulatory issues are emerging regarding drug first-line treatment of DLBCL.45–47Until now, however, intensifica- development, marketing authorization, and reimbursement for tion of treatment, the addition of maintenance therapy, the intro- new drugs in adult ALL, which are treated with complex com- duction of immunomodulatory or novel-targeted agents have bination therapies and management strategies. Support struc- neither improved outcomes in unselected patient populations tures developed for pediatric ALL1 should be extended to adult nor identified selected subgroups of patients, who could benefit ALL, in collaboration between national competent authorities, from a new combination. On the other side, these studies have Institutional Review Boards, pharmaceutical companies, and been able to reduce toxicity without affecting efficacy in patients academic study groups. The evaluation of new compounds in at low-risk48 and new initiatives have been proposed to guide rare molecular subgroups of ALL will require European-level treatment strategy based on early response, particularly based collaboration with the European Medical Agency and inter- on PET-CT.49,50 In addition, several European studies evaluated group data-sharing, as in the Harmony IMI initiative, https:// new agents or new combinations.51–55 The development of CAR-T www.harmony-alliance.eu. New strategies for clinical trial cell therapy in relapsed and refractory DLBCL was a revolution design must be developed in concertation with patient repre- initiated in the United States, but the networking of European sentatives, and there is an urgent need to support the successful treatment centers has made it possible to observe a large number infrastructure of European academic multicenter study groups of patients and continue to evaluate this method in real life. through funding programs. In AYA, DLBCL is the second most common aggressive In the next years, these challenges will become evident for B-NHL. Outcome for DLBCL patients improved in recent clin- the integration of new monoclonal antibodies and cell therapies ical trials using Bukitt-type treatment regimen.56 Analogue to into first line. Several clinical trials are ongoing in Europe and adults, genetic sub-classification will support subgroup identifi- worldwide requiring harmonization to enable future meta-anal- cation and treatment modulation.57 yses.37–39 The scientific questions do not only focus on the impact of a single compound but new combination strategies and the Proposed research for the Roadmap role of current drugs, risk stratifications, and approaches like The Roadmap is in line with the one proposed five years ago. HSCT. One major research question will certainly focus on the We have now tools that will allow to further investigate mecha- future role of HSCT in adult and pediatric ALL. nisms of DLBCL pathogenesis including novel models and leverage For Ph+ ALL the selection of TKIs, the efficacy of chemother- high-throughput functional screens (genetic and pharmacological) apy-free regimens,40 indications for change of TKI, the impact to identify unappreciated vulnerabilities and guide future drug of MRD measured with different methods, the role of immuno- development. Recent advances in understanding of the genetic het- therapies, and HSCT will be important research questions. erogeneity of DLBCL that led to the definition of molecular sub- One priority for the research agenda is the management of groups could be accessible to existing or newly designed targeted T-ALL and T-LL. Less progress has been made regarding the therapies. The ability to recognize these subgroups in a reliable, biologic characterization and prognostic classification, with a reproducible but also timely manner will be an important chal- relative paucity of promising new compounds41 and immuno- lenge to introduce these drugs in the first-line treatment in AYA. therapeutic targets. Whereas the overall prognosis of T-ALL is The availability of circulating tumor DNA (ctDNA) could help to quite favorable, new approaches are urgently required for poor characterize the genomic profile of the disease. prognostic subgroups since survival after relapse is rare. The next wave of technologies will allow to capture single cell and spatial heterogeneity and to comprehensively understand Anticipated impact of the research the role of the tumor microenvironment and the “fitness” of the Future treatment will still be based on current very successful immune system. The knowledge of the immunological synapse standards, however, targeted therapies including immunother- will be invaluable to better address treatment with immuno- apies will be increasingly implemented. These should improve modulatory drugs, bispecific antibodies, and CAR-T cells. These the prognosis of high-risk patients but also significantly reduce data should allow the construction of a new prognostic indices treatment-related morbidity for patients of all ages, and espe- integrating multiomics and clinical characteristics. cially for long-term survivors of childhood ALL. In addition, It will be of interest to monitor early treatment response individualized drug dosing may prevent underdosing and hence to guide subsequent treatment, either in the direction of a may reduce the risk of relapse, while preventing over-dosing and reduction or toward a different strategy. The combined use associated toxic side effects. of PET-CT and ctDNA will be key tools for this longitudinal assessment. The disappointing results of large studies aiming to improve DIFFUSE LARGE B-CELL LYMPHOMA AND BURKITT first-line treatment and the detected genetic and clinical hetero- LYMPHOMA geneity of DLBCL underline the limit of “one size fits all” in Introduction this disease. Tailoring therapeutic approaches of specific clini- Diffuse large B-cell lymphoma (DLBCL) is the most common cal, morphological, and molecular entities will require collabo- clinically aggressive lymphoid neoplasm. In addition to the most ration of European national co-operative groups and evolution common DLBCL “not otherwise specified” type, comprising of the methodology how clinical trials are performed. Similarly, germinal center B-cell, activated B-cell like subtypes, the 2016 real-life studies, based on the observation of a large number of WHO classification recognizes specific variants (eg, T-cell/his- patients, will be very useful in the evaluation of new treatments, tiocyte-rich large B-cell lymphoma, EBV-positive DLBCL) and especially those that are very expensive. high-grade B-cell lymphoma with MYC and BCL2 or BCL6 translocations as a separate entity (Figure 1).42 Anticipated impact of the research These research directions aim at a better understanding of European research contributions biology and a better management of patients with DLBCL. The European researchers have contributed to international efforts personalized treatment, more effective and safer, for DLBCL redefining molecular classifications of aggressive B-cell lymphoma patients is not yet in our hands. A close collaboration between beyond the transcriptionally cell of origin classification to identify investigators, academic researchers, pharmaceutical companies, genetically defined subtypes that suggest a specific lymphomagen- and patient associations will be necessary to achieve this goal esis, corresponding to a distinct outcome and allowing to consider and allow this progress to be shared throughout Europe. 4 (2022) 6:6 www.hemaspherejournal.com Figure 1. Implications of the DLBCL genetic subtypes for pathogenesis and therapy. Summary of the relationship between DLBCL COO subgroups and the genetic subtypes (left). The genetic themes, phenotypic attributes, clinical correlates, and treatment implications of each subtype are shown at right. Prevalences were estimated using the NCI cohort, adjusting for a population-based distribution of COO subgroups (see STAR Methods).42 dep. = dependent; DLBCLs = diffuse large B-cell lym- phomas; FDC = follicular dendritic cell; IZ = intermediate zone; LZ = light zone. Reprinted from: Cancer Cell, Vol 37/issue 4, Authors Wright GW, et al, A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications, Pages 551-598, Copyright 2020, with permission from Elsevier. MANTLE CELL LYMPHOMA ASCT was shown to improve PFS,60 and in the 2nd European MCL Network Elderly trial, the addition of lenalidomide to rit- Introduction uximab maintenance (R2) prolonged PFS compared with rit- Mantle cell lymphoma represents approximately 7% of all uximab alone.61 European groups have also explored the use non-Hodgkin lymphomas (NHLs) and is characterized by the of BTK and BCL2 inhibitors in untreated patients with MCL, translocation t(11;14)(q13;q32) and the overexpression of such as the combination of rituximab and ibrutinib (IR) in low- CCND1 (Figure 2). From a tumor biology perspective, two risk MCL by the Spanish group,62 and the addition of vene- molecular subtypes can be defined; the conventional, nodal toclax consolidation after R-BAC63 in elderly high-risk MCL. type, typically characterized by aggressive clinical course and Moreover, a number of novel combinations have undergone requiring immediate treatment, and the non-nodal, often leu- study in relapsed/refractory MCL among co-operative groups in kemic type, with more indolent clinical behavior. The standard Europe, including temsirolimus, an mTOR inhibitor, in combi- approach for younger patients is based on immunochemother- nation with R-bendamustine,64 ibrutinib-R2,65 venetoclax-R2,66 apy, which consists of rituximab and CHOP-like or high-dose as well as obinutuzumab in combination with venetoclax and Ara-C–containing regimens followed by high-dose treatment ibrutinib.67 with autologous stem cell transplantation (ASCT) and ritux- Furthermore, European groups have been instrumental in the imab maintenance. Elderly patients are usually treated with identification of the molecular biology and genome and epig- rituximab and CHOP (R-CHOP) or R-bendamustine, fol- enomic alterations of MCL subtypes68 and specific molecular lowed by rituximab. During the last 5 years, several novel high-risk groups of patients, particularly defined by the presence agents have been introduced and approved for the treatment of mutations of TP53, but also other genetic aberrations, includ- of relapsed and refractory MCL; the immunomodulatory ing KMT2D mutations and CDKN2A deletions.69–71 agent lenalidomide, the BTK inhibitor ibrutinib, the BCL2 inhibitor venetoclax, and most recently, brexucabtagene auto- leucel, a CAR-T cell product. Many other agents are undergo- Proposed research for the Roadmap ing clinical development in MCL, including newer generations A number of phase 3 trials, with potential to change clin- of BTK inhibitors, bispecific T-cell engagers, and antibody ical practice in untreated patients with MCL, are ongoing drug conjugates.58 in Europe. These include the TRIANGLE trial, assessing the impact of addition of ibrutinib in induction and maintenance, European research contributions as well as challenging the use of ASCT72; the European MCL During the last 5 years, European co-operative groups have Network Elderly R2 trial, evaluating the addition of cytara- contributed significantly to the development of treatment strat- bine to standard R-CHOP induction; and the ENRICH trial, egies for the young as well as the elderly MCL population. In comparing a chemo-free regimen, ibrutinib-rituximab, to stan- the French LyMa trial, rituximab maintenance post ASCT has dard chemoimmunotherapy in elderly patients. Taking this one been shown to prolong overall survival in the first-line setting, step further, ibrutinib-rituximab is compared with venetoclax- a finding now implemented as standard practice.59 A few tri- ibrutinib-rituximab in a randomized phase 2 trial, the OASIS als have also explored the use of lenalidomide maintenance. II. Finally, a randomized trial will compare this triple combina- In a phase 3 trial by the Italian FIL group, lenalidomide post tion to a chemotherapy standard (MCL elderly III). 5 Dreyling et al Research Roadmap: Malignant Lymphoid Diseases Figure 2. Proposed model of molecular pathogenesis in the development and progression of major subtypes of mantle cell lymphoma.58 Reprinted from Blood, Vol 127/issue 20, Authors Swerdlow SH, et al, The 2016 revision of the World Health Organization classification of lymphoid neoplasms, Pages 2376-2390, Copyright 2016, with permission from Elsevier and/or The American Society of Hematology. Other venues of development include ambitions to develop European research contributions response adapted treatment strategies, based on MRD66; incor- European groups have led the way on both the biological and poration of the new knowledge emerging from biology stud- therapy front. ies into risk-based strategies, specifically targeting biological Major contributions to unraveling the pathogenesis of high-risk populations such as TP53-mutated MCL; strategies to include better understanding of the premalignant dynamics of improve outcome for BTKi-refractory disease; as well as real- FL development, detailed description of the genetic landscape world evidence studies, based on the high quality, nation-wide of FL, the contribution of nongenetic determinants such as the registers present in many European countries. microenvironment and the complexity of genetic heterogeneity and evolution. Emerging data demonstrate that mutations pres- Anticipated impact of the research ent in tumor cells are implicated in phenotypic and functional Mantle cell lymphoma is a rare lymphoma subtype but also remodeling of the FL microenvironment, favoring immune a disease where there is an abundance of novel agents with high escape mechanisms, and providing a favorable niche for FL cell activity. We expect that incorporation of novel-targeted agents survival. Furthermore, the adoption of single-cell technological in front-line combinations ultimately will lead to improvement approaches illustrate that the continuum of B-cell states are in survival, and possibly even cure, while reducing early and late broader than the traditional germinal center cell of origin of FL. side effects. Several new prognostic models including m7-FLIPI,75 PRIMA-PI,76 and PRIMA 23-gene77 have been developed to aid patient risk stratification. European studies have led in the FOLLICULAR LYMPHOMA widespread use of immunochemotherapy78 and introduction of Introduction novel monoclonal antibodies,79 resulting in improvement in sur- Follicular lymphoma is the second most common lymphoma, vival with median overall survival for FL now 15–20 years. More with the highest and increasing incidence in Europe (approxi- recent trials have focused on chemotherapy-free regimes targeting mately 3.14 cases per 100,000 persons per year).73 FL represents the FL cells and the tumor microenvironment leading to the first a heterogeneous disease both clinically and biologically. The approval of the immunomodulatory agent lenalidomide for the chromosomal translocation t(14;18) and recurrent alterations in treatment of FL.80 Other studies led or with major contributions epigenetic regulators are pivotal genetic hallmarks. FL primarily from European investigators have led to approvals for FL of PI3- affecting older adults, the disease is characterized by a variable kinase inhibitors, tazemetostat, the first epigenetic drug approved clinical course spanning from those patients exhibiting an indo- in this disease, and chimeric antigen receptor (CAR) T cells. lent behavior to high-risk patients with shortened survival such as those who progress within 24 months of initial immunoche- Proposed research for the Roadmap motherapy (POD24) or undergo histological transformation. Although major advances have been made in determining Guidelines for the diagnosis and treatment of FL were outlined the molecular pathogenesis of FL and attempts have been to recently by the European Society for Medical Oncology.74 There use this information to develop prognostic scores, it is still not is no consensus on standard of care particularly for relapsed possible to develop scores, which are robust enough or widely disease, but there is increased interest in novel-targeted agents applicable to impact clinical management. European researchers and immunotherapeutic approaches. are prominent in studies examining the histopathologic changes 6 (2022) 6:6 www.hemaspherejournal.com in the microenvironment and collaborative studies have been of individual patients and patient cohorts and the ability to performed examining the changes in the tumor microenviron- have these tests widely available for patients in Europe will ment and how these changes relate to genetic and epigenetic allow the most appropriate treatment to be selected within changes in the tumor cells (Figure 3). Europe now leads the way clinical trials investigating novel-targeted therapeutic agents. in the use of “big data” to assess the impact of molecular events This will also allow identification of robust biomarkers for on outcome but very large cohorts are required to enable all the monitoring response to treatment to allow a precision medi- different parameters to be evaluated. The HARMONY project cine strategy to be applied to improve the survival and quality is now collecting molecular and clinical data from patients with of life of patients with FL. FL, but the number of samples in the database lags behind other disease but this is now being given increased priority. MARGINAL ZONE LYMPHOMA: EXTRANODAL, NODAL, AND 1. Continue work on the molecular mechanisms spanning SPLENIC FORMS early disease development to transformation, should be a Introduction common goal.77,81–85 Better understanding of the biologi- Marginal zone lymphomas (MZLs) are a diverse group of cal underpinnings of different clinical phenotypes and the clinicοpathological entities, comprising extranodal (also called lymphoma “reservoir,” which likely contribute to subse- MALT lymphoma—EMZL), nodal, and splenic (SMZL) forms. quent relapse is needed.83 A key issue would be performing Most MZLs are indolent disorders, whose ontogeny is closely both genetic and microenvironment analyses on longitudi- linked to autoimmune disorders and chronic infections.1 MZLs nal or paired FL biopsies to obtain an integrated view on are often manageable with a “watch and wait” strategy, and, bidirectional dependency.86,87 generally, exhibit excellent outcomes when treated with conven- 2. A biobank of lymph node and other biopsies linked to the tional anticancer therapies. That said, open issues exist regard- clinical database should be available with protocols for ing both the biology and the treatment of MZLs, prompting standardized sampling and storage adapted to genomic research that would advance the field toward personalized and functional assays. This requires ethical approval and management. consent from patients for the procurement and storage of excess tissue from lymph node biopsies at the time of pre- sentation and of particular importance are serial samples European research contributions obtained from patients in a longitudinal manner at each An important European milestone concerned the more relapse and progression and there may be value in multiple precise characterization of the molecular landscape of biopsies to assess intra-patient heterogeneity.88 MZL. Next-generation-sequencing studies confirmed previ- 3. A database (a coordinated pan-European registry) that ously defined pathways involved in MZ lymphomagenesis can be accessed by all research partners, containing the (eg, NF-κB and NOTCH), while also highlighting the dis- biological and clinical information collected for each par- tinctive features of each entity. Distinct mutation patterns ticipating patient, should be made available. This can be were observed per primary site in EMZL,92–95 and distinct provided with the HARMONY platform among others mutations in G-protein coupled receptors, not yet reported and increased data on FL patients into the database should in human malignancies, have been described.93 The immu- be encouraged. nogenetics of MZLs have been better delineated, reveal- 4. Robust biomarkers (both prognostic and predictive) ing distinct biases in different MZLs, strongly supporting should be developed to aid upfront identification of high- unique antigen exposures.96,97 Remarkable associations risk FL patients and prioritization of specific therapies to have been reported between particular genomic aberrations specific patient groups.89 and the immunogenic background of MZL, suggesting an 5. Assays to assess the persistence of MRD should be more intricate cross-talk between the malignant cells and their widely available and evaluation of emerging “liquid microenvironment.98–100 biopsy” and ctDNA assays to provide a means of dynamic Several European academic trials shaped the treatment risk assessment should be explored.90,91 landscape of MZL in the last 5 years. A specific MALT 6. Novel animal models that recapitulate disease features and lymphoma prognostic score called “MALT-IPI,” based on allow preclinical investigation could also be developed. No the IELSG-19 data set and three further European valida- good animal models of this disease are currently available, tion cohorts has been developed.101 The negative impact of limiting research and drug development in this disease. early progression of disease within 24 months (“POD24”) 7. Academic clinical research should address issues related after start of therapy on survival was confirmed for MALT to the costs and benefits of different therapeutic options lymphoma patients.102 First-line standards for MALT lym- including the optimal imaging and the potential value of phoma patients in need of systemic treatment have been PET scans in this FL into an integrated approach to follow confirmed by long-term results published for chlorambu- this disease.91 This is important to ensure equitable access cil-rituximab (IELSG-19 trial)103 and bendamustine-ritux- and affordability to emergent therapies and diagnostic tools. imab (MALT 2008-01 trial).104 The AUGMENT phase III 8. Increased attention should be paid to optimize strategies in study has shown that lenalidomide-rituximab was associ- the elderly population who carry the major burden of this ated with durable responses in MZL patients,105–107 and this disease. combination is a salvage option mentioned in the ESMO guidelines.108 Encouraging activity has been reported for the second generation anti-CD20-antibody ofatumumab ± Anticipated impact of the research bendamustine,109,110 and for the small molecules copanlisib The current lack of understanding the nature of the lym- and umbralisib.111 High-response rates have been reported phoma “stem cell,” and the events involved in disease pro- in SMZL patients treated with rituximab-bendamustine in gression and transformation negatively impact our ability the BRISMA/IELSG36 trial,112 whereas the question on the to cure this disease. The research plans above hold the key role of rituximab maintenance in MZL patients remains to understanding the key molecular events in disease evolu- open.108,113 The efficacy of novel antiviral agents for the treat- tion and progression to help identifying key targets for opti- ment of hepatitis C virus-triggered MZLs has been suggested mal therapeutic intervention, and in particular to target the by European retrospective studies114 and the first prospective tumor microenvironment. The characterization of the genetic, trial in this setting, called FIL-BART. Concepts “off-main- genomic, proteomic, transcriptomic, and metabolomic profile stream” are exemplified by data on intralesional rituximab 7 Dreyling et al Research Roadmap: Malignant Lymphoid Diseases Figure 3. Research roadmap in FL. Understanding how healthy B cells transform through premalignancy, to malignancy and how there is persistence of MRD after treatment are key to biologic features; good animal models of FL are key to better understanding pathogenesis and development of novel agents for treatment; development of robust predictive and prognostic biomarkers key to rapid assessment of the utility of new agents; measurement of ctDNA is import- ant to characterize the disease, allow precision medicine approaches and measure MRD; assessing the cost benefit of an integrative approach to treatment of this disease will benefit patients and health technology assessment; integrated database and biobank will provide a pan-European resource to advance study in FL. ctDNA = circulating tumor DNA; FL = follicular lymphoma; MRD = minimal residual disease. supplemented with autologous serum against MALT lym- co-operation will promote the establishment of novel therapeu- phoma of the conjunctiva.115 Finally, first data of CAR-T-cell tics in these rare lymphoma entities. therapy for MZL were presented recently; assessment on a larger number of patients and longer follow-up is expected. WALDENSTROM MACROGLOBULINEMIA Proposed research for the Roadmap Introduction 1. Comprehensive characterization of the biological back- WM incidence is usually estimated at around 0.4 per 100,000 ground of the malignant cells, complemented by functional person-years, most patients being diagnosed after the age of 65 analysis of their interactions with the respective tumor years. Fixed duration immunochemotherapy (ICT) is widely microenvironments, including micro-organisms. used since the mid-2000s. Used as first-line therapy, median 2. Dissection of disease trajectories and clonal evolution, PFS ranged from around 3 to 5 years. A characteristic muta- starting from putative premalignant conditions associ- tion in the MYD88 gene is found in 90–95% of patients. This ated with chronic infections or autoimmunity to entities abnormality pointed out the role of TLR and BCR pathways, of undisclosed biological background and uncertain clin- among others. A wide range of other molecular abnormalities ical relevance (eg, clonal lymphocytosis of MZ origin) to has also been identified, the most frequent being mutation in transformation. the CXCR4 gene. Meanwhile, ibrutinib, the first-in-class btk 3. Homogenization of antitumor response assessment, espe- inhibitor dramatically improved PFS in refractory/relapsing cially in view of the particularity of extranodal disease and (RR) patients (4 years median PFS obviously better than previ- nonglucose avid lesions at PET, with implications for both ously reported estimates in RR patients).116 However, ibrutinib routine practice and clinical trials. cannot be stopped. The complexity of the genomic landscape 4. Identification of ssurrogates of established endpoints in suggests that the disease is likely a consequence of a multistep clinical trials, particularly for novel therapeutics, since process and that there is a lot of ways to improve outcome with conventional endpoints, like overall and complete response combination therapy (Table 1). rates, do not fully capture patient outcomes in MZL. 5. Identification and validation of novel therapeutic European research contributions approaches aimed at cure, a still unattainable goal, through Swedish teams reported on the frequency of familial WM clinical trials sspecifically focused on MZL patients. and on the association with an underlying autoimmune con- dition, while several Spanish reports deciphered the multistep Anticipated impact of the research pattern of onset of asymptomatic WM, and then symptomatic Improved knowledge of MZL biology will result in refined WM as well as the occurrence of histological transformation diagnosis and identification of novel druggable targets. into an aggressive lymphoma. Furthermore, this group identi- Understanding the involved antigens, pathogenic mechanisms, fied a WM-specific phenotype that can be used to assess cellu- altered molecular pathways, and microenvironmental inter- lar response in the bone marrow. Two teams of the European actions will promote personalized therapies with better safety consortium established the international scoring system for and efficacy profiles. Standardization of efficacy endpoints and WM. A revision of this system has been recently proposed by assessment of surrogate markers will enable reliable comparison 2 teams of the consortium. European teams also reported on between clinical trials. Importantly, only extensive European the clinical characteristics of some IgM-related disorders such 8 (2022) 6:6 www.hemaspherejournal.com as neuropathy, acquired von Willebrand syndrome, amyloidosis, patients receiving current treatment approaches, including ICT and the molecular characteristics of the underlying clonal dis- for most of these, at least at first-line therapy. order in the cold agglutinin disease.116 Beside guidelines, single Improved baseline prognostic assessment in combination centers or single co-operative groups studies, European countries with dynamic tools should improve the design of future trials in demonstrated their ability to merge their efforts in large-scale the area of new targeted therapy. These tools should also facil- multinational studies designed for this rare disease. Following itate the identification of particular unmet medical needs and the WM1 trial, the European Consortium for Waldenstrom’s conversely the identification of clinical settings where the mor- Macroglobulinemia is the largest of its kind and has proven that tality may not be different from that of the general population, randomized trial with appropriate power are feasible in this rare useful information in case of limited access to health resources. disease. An example is the INNOVATE trial, which has led to Finally, during this pandemic, the response to vaccines should the approval of Rituximab/Ibrutinib in WM.120 also be particularly studied. All these studies are milestones for improving the quality and Proposed research for the Roadmap the interpretation of efficacy and safety data provided by large Prolonged delivery of novel therapy improved the out- multicenter European trials. come of symptomatic WM patients, compared with the out- The future will rest on a better understanding of the disease, come observed after fixed duration immunochemotherapy. the following issues, among others, remained to be checked: the The main goal is now to identify a time-limited novel therapy relationship between the neoplastic B-cell and its microenviron- combinations. ment (Single-cell analyses), the mechanism of clonal evolution (using sequential material). This objective requires a European For the present biobanking network for storing material collected during clini- Systematic adjunction to clinical trials of planned biological cal trials or retrospective studies of interest, once the material is studies along with sharing of baseline biological material when- adequately sampled, processed and annotated. In addition, vali- ever possible is a major challenge. The availability of this bio- dation of hypotheses provided by these studies will also require logical information should improve discrimination of currently appropriate preclinical models. available scoring systems either for symptomatic or asymp- At any time, it should be reminded of the importance of epi- tomatic patients. The statistical analyses will have to take into demiological studies for identifying potential environmental account that one-third of patients with symptomatic WM will risk factors involved in any part of the multistep process of the not die from the disease. In addition, most molecular abnormal- disease or its clonal evolution. Accurate assessment of the qual- ities with potential prognostic significance, including the myd88 ity of life is also a major endpoint, and there is a need for a wild type status, are found in only small subgroups of patients specific form specially designed for WM. In Europe, national (<5–10% of patients); the CXCR4 status identified a significant patient organizations merged their efforts in the European subgroup of patients but the validation of its prognostic value Waldenstrom Network. is still pending.120 Using the information recorded during the evolution (such as response to treatment) and events that happened mean- CHRONIC LYMPHOCYTIC LEUKEMIA while (such as progression) is another way to improve prog- Introduction nostication. Indeed, current response criteria have a limited CLL is the most common leukemia among adults in prognostic value. Confirmation of the likely prognostic role Europe.122,123 The disease is biologically and clinically complex of flow-cytometry or molecular assessment (including cell-free and can serve as a model system for cancer in general, in par- DNA analyses) of malignant cell depletion in blood or bone ticular in the context of senescence and clonal evolution.124,125 marrow is mandatory. In addition, the identification of opti- Based on a better understanding of the disease biology, targeted mal cutoff values and the integration of this new parameter in treatments have been developed that have revolutionized clinical new response criteria with validated prognostic values is also management, yet have led to additional research questions.126,127 a major challenge. This task is probably associated with the definition of surrogate endpoint in place of now unattainable European research contributions endpoint such as overall survival and/or PFS, especially in the European contributions have been of importance with regard context of first-line therapy. to biology as well as therapy of CLL, focusing in particular on As already done in other disorders,121 it is likely that a large the following aspects. multinational study using specific bioinformatics tools such as • Molecular mechanisms of pathogenesis, evolution, and artificial intelligence methodology will be required for this pur- resistance pose. Because of the large number of events and the appropriate • Biological markers for prognostication, prediction, and as follow-up required, this analysis will probably be carried out on therapeutic targets Table 1. Summary of Main Steps in the Understanding and the Management of Waldenstrom Macroglobulinemia Time Scale Etiology/Epidemiology Cytogenetic and Genomic Cytometry/Pathology Prognosis Treatment Present Preclinical model of mice with Prospective biobanking Identification of surrogate Fludarabine vs. Chlorambucil118 MYD88(L252P) mutation117 endpoint of survival Optimal method of detection Optimal threshold and Assessment of quality of life Ibrutinib in previously treated WM of residual disease? response criteria patients119 Validation of the prognostic role The INNOVATE trial : Rituximab of molecular landscape Ibrutinib vs. Rituximab alone120 Future Environmental studies Prognostic assessment of patients treated with ibrutinib first line Preclinical models Dynamic prediction, New Efficacy of vaccines response criteria WM: Waldenstrom macroglobulinemia. Only published original reports or scientific works reported as an abstract since <1 y were considered for this table. 9 Dreyling et al Research Roadmap: Malignant Lymphoid Diseases • Treatment strategies of improved efficacy and tolerability Apart from CLL progression, transformation into aggressive aiming at cure histology (Richter transformation) is a phenomenon of largely unclear etiology and detrimental outcome.135 Prevention and Proposed research for the Roadmap overcoming resistance development, clonal evolution or disease The cell of origin and initial transforming events of CLL remain transformation are critical issues for future management. largely enigmatic. Monoclonal B-cell lymphocytosis is a condi- Although not only efficacy but also tolerability of the tar- tion that appears to precede CLL but the evolution to CLL is geted agents is favorable, there are adverse events, which are rare. Better understanding of the cell of origin and initial transfor- partly characteristic for the novel agents, and need optimi- mation steps may lead to diagnostic and therapeutic advances.128 zation by improved management and further compound The immunoglobulin (Ig) receptor is key in the pathogenesis development.136 In particular, prevention and treatment of of the disease, through antigenic or cell-autonomous signaling. infections, and hematological or cardiovascular side effects The mutational status of the IGHV genes and their stereotyped remain research priorities, as they are leading causes of mor- subsets indicate pathogenic mechanisms, are of prognostic bidity and mortality. Because CLL predominates in the elderly, value and can serve for patient stratification. Further research is the proportion of older people with CLL will increase and needed to improve all of these aspects.129,130 the development of specific tools to assess comorbidities and Ig and other surface receptor biology highlight the impor- geriatric status should be pursued. The optimal management tance of the extracellular compartment and the microenviron- of CLL in the COVID-19 era needs international research ment. Of note, CLL cells deprived of their in vivo environment collaboration.137 die of spontaneous apoptosis. Modeling this interaction of CLL Overall, it will remain of key importance for future advances with its environment remains an important issue.131 to combine laboratory and clinical research in a fully integrated Cell intrinsic abnormalities driving CLL have been defined and truly translational approach. This should be reflected in the such as genomics aberrations, gene mutations, methylation setup of experimental concepts and clinical trial designs, which abnormalities, and gene expression deregulation. Among these, must not stand in isolation, with the systematic collection of TP53 abnormalities and IGHV mutation status/Ig structure biological material and information also during long-term fol- are currently the key factors in treatment stratification, but a low-up and at progression. From a general perspective, while wealth of additional abnormalities of pathogenic, prognostic, this outline is focused on CLL, similar principles can be applied and potentially predictive importance remain to be defined.125,132 to the heterogeneous range of all chronic lymphoproliferative This is in particular relevant in the light of novel treatment disorders. approaches for which prognostic as well as predictive factors need to be established and resistance mechanisms due to the Anticipated impact of the research acquired abnormalities of target genes are becoming of impor- Success in laboratory and clinical CLL research has led to tance. Both, hypothesis-driven focused approaches (ie, individ- improved disease understanding and patient management. ual pathways and genes) and global methodologies (ie, “omics” Specific impact on CLL is an improved patient outcome, with approaches) as well as integration of “big-data,” for example, by the overall aim of cure or at least prevention of CLL-related machine learning algorithms are needed.124,125,133 morbidity and mortality. On a larger scale, CLL research can The importance of Ig and other signaling pathways as well serve as a role model for improved patient management in other as apoptosis regulation have led to the development of targeted conditions, based on the successful translation of disease biol- treatments focusing on CD20, BTK, PI3K, and BCL2.126 These ogy into personalized therapy. approaches have revolutionized the treatment of CLL and chemo- immunotherapy plays a minor role only in the absence of TP53 aberrations and presence of mutated IGHV.129,132,133 Among the T-CELL AND NK-CELL LYMPHOMA novel treatment approaches, head-to-head comparisons of single Introduction agents and in particular of combinations are a focus of research. Lymphomas arising from mature T- and natural killer (NK)- Moreover, the best combinations of these agents and the opti- cells—collectively, peripheral T-cell lymphomas (PTCLs)—are mal schedule ranging from continuous therapy to fixed duration rare, heterogeneous, and poorly understood malignancies, treatment or response-guided (ie, by MRD) approaches have not with poor survival outcomes for the majority of patients. The been determined and are a priority in clinical trials. Although 2017 update of the WHO classification incorporated advances a comprehensive overview of (European) studies is beyond the in understanding of the cell of origin and molecular genetics scope of this article, many recent trials sponsored by industry (eg, for some entities. However, there is considerable overlap in Glow, Sequoia, Captivate, Sequoia, Unity U2) and investigators/ the genomic landscapes and the existing classification of many study groups (eg, Vision HO141, Filo V+I vs. FCR, UK NCRI PTCLs as “not otherwise specified” (NOS) remains unsatisfac- FLAIR, GCLLSG CLL13/Gaia, and CLL17) are under way in tory. Preclinical models remain limited, further hampering devel- Europe. This includes also the next-generation agents targeting opment of biologically informed effective therapies. Overall, these pathways whose development is under way. In particular, therapeutic progress has been modest. when comparing fixed duration versus continuous therapy, the sole focus on PFS1 as an endpoint is inadequate and PFS2 as well as OS comparisons after retreatment are needed. European research contributions Many patients still experienced disease progression on The ECHELON-2 study,138 an international effort co-led by or after treatment with targeted agents and optimization of European investigators, demonstrated the superiority of CHP sequencing of individual agents or combinations for individ- plus BV, as compared to CHOP, for patients with Anaplastic ual patients defined by host (eg, comorbidities, comedication) Large cell Lymphoma (ALCL). These data led to EMA approval and disease (eg, genetics and other biology) characteristics, is of CHP+BV for ALCL; a paradigm-shift in first-line therapy a key future question for clinical trials.127,134 In disease relapse, for this disease. Insights into biological risk stratification in a number of resistance mechanisms derived from extracellu- ALCL, including potential prognostic significance of DUSP22 lar but mostly cell intrinsic factors such as mutations of tar- and TP63 rearrangements, have not yet impacted clinical deci- get genes have been identified. The role of T-cell therapy (eg, sion making. Another large international phase III RCT, led CARs, bispecific antibodies, stem cell transplantation strate- by the LYSA group, reported first data from the Romidepsin gies) in the management of refractory disease merits further (Ro)-CHOP versus CHOP study. However, the primary end- investigation. point was not met; the addition of Romidepsin to CHOP did 10 (2022) 6:6 www.hemaspherejournal.com not improve PFS.139 In a phase 2 study (REVAIL) of lenalido- interventions informed by a refined understanding of specific mide with CHOP, as first-line treatment for older patients with disease vulnerabilities. angioimmunoblastic T-cell lymphoma (AITL), the primary end- point (complete metabolic response rate) was not met. However, Anticipated impact of the research this LYSA study described an association between DNMT3A The potential impact of ongoing and planned research pro- mutations and inferior PFS.140 The role of autologous stem cell grammes in PTCL is substantial. More biologically precise diag- transplantation (ASCT) for PTCL in first remission remains noses, refined prognostication and opportunities for patients to unresolved.141 A German and French co-led study randomised access more effective therapies leading to improved survival, are 104 PTCL patients to undergo either ASCT or alloSCT in first realistic goals. Nevertheless, significant challenges remain given remission. No difference in significant 3-year EFS was observed, the rarity of these entities, their biological heterogeneity, and with relapse representing the dominant cause of failure with the practical difficulties of enrolling many patients on obser- auto-SCT, contrasting with no relapses in the alloSCT group vational or interventional research protocols. It is particularly but high rates of non-relapse mortality.142 For r/r PTCL with a crucial for this rare and heterogeneous group of malignancies TFH phenotype, the French LYSA group led an international that pan-European academic and commercial collaborations are phase 3 study (ORACLE) investigating orally administered broadened and strengthened. Importantly, clinical investigations 5′-Azacytidine (CC486); results are awaited. As a pivotal proof should remain faithful to the concept of translational science, of concept, an anti-TRBC1 chimeric antigen receptor (CAR) maximizing the value of data derived from each patient studied, T cell was engineered to recognize and kill TRBC1+, but not to inform the next generation of clinical research and ultimately TRBC2+, T cells in a preclinical model143 paving a path toward improve outcomes for all patients with lymphomas of T- and adoptive cellular therapy for PTCL. For extranodal NK/T lym- NK-cell origin. phoma, data from the Italian-led International T-cell project demonstrated improved survival outcomes, attributed to wide- spread adoption of nonanthracycline-based protocols, use of LYMPHOMA AND IMMUNE DEFICIENCY (INCLUDING L-asparaginase and radiotherapy.144 AIDS, POSTTRANSPLANT, AND DRUG-INDUCED Investigators from France and Switzerland established that IMMUNODEFICIENCY) a subset of PTCL-NOS cases display a TFH immunopheno- type and similar genetic features to AITL.145 Moreover, AITL Introduction and related TFH lymphomas harbor diverse recurrent acti- The incidence of HL and NHL, in patients with congenital vating mutations in genes related to TCR signaling.146 Belgian or acquired immune deficiencies, is higher than in the immu- researchers discovered novel fusions transcripts FYN-TFNAIP3 nocompetent population. AIDS-associated lymphomas are the and KDHRSB1 hijacking TCR signaling in PTCL-NOS,147 most representative among them. The incidence of NHL initially while European researchers contributed to international studies fell in the cART era but has now stabilized, whereas that of describing novel GEP-defined PTCL subgroups.148 A Swiss-led HL has increased.156,157 Posttransplant lymphoproliferative dis- study identified mutation-induced inactivation of the methyl- orders (PTLD) include a range of diseases ranging from benign transferase SETD2 gene as a genomic hallmark of monomor- proliferations to malignant lymphomas.158 The management of phic epitheliotropic intestinal T-cell lymphoma (MEITL),149 lymphomas in immunosuppressed patients differs according to with frequent alteration of the same gene in Hepatosplenic the cause of the immunosuppression. In HIV-infected patients, T-cell lymphoma (HSTL).150 Substantial contributions to the the extensive use of cART has allowed these patients to be characterization of breast implant-associated ALCLs, were treated with identical schedules of immunochemotherapy as made by European groups: delineating distinct clinical presen- those used in the general population (together with cART and tations151 and new descriptions of the genetic landscape.152,153 adequate prophylaxis of opportunistic infections).159 In PTLD, French researchers developed targeted MLPA-based assays to the first step is the removal of immunosuppressive therapy, fol- characterize gene expression signatures of PTCL entities154 and lowed by anti-CD20 immunotherapy, moving quickly to stan- to detect known fusion transcripts;155 these findings should dard immunochemotherapy schedules if response is not rapidly enable improved characterization of PTCL in routine practice. achieved.160,161 Proposed research for the Roadmap European research contributions The overarching research priority is to develop more effec- Several national groups from European Union countries tive therapies to cure a higher proportion of patients with T have conducted phase II trials showing similar results in the and NK lymphomas at first attempt. A deeper understanding treatment of HIV-related lymphomas in the cART era. The of disease pathobiology is necessary to progressively refine most frequent schedules used for DLBCL are R-CHOP, and diagnosis and prognosis. The molecular complexity of PTCL R-EPOCH (rituximab, etoposide, prednisone, vincristine, biology requires a comprehensive understanding of disease cyclophosphamide, and doxorubicin); for BL the most fre- processes and tumor heterogeneity. To this end, the European quent schedules are RCODOX-M/IVAC (rituximab, cyclo- collaborative TRANSCAN-2 project (EuroTCLym) will under- phosphamide, vincristine, doxorubicin, and methotrexate/ take integrated analysis of PTCL pathobiology on clinically ifosfamide, etoposide, and cytarabine), LMB, NHL2002, annotated biopsies. Functional studies from representative pre- Burkimab, and dose-adjusted R-EPOCH, among others.162 A clinical models also remain crucial. Clinical trial design must new prognostic score for HIV-related lymphomas in the ritux- adapt to accommodate multiple biologically defined subgroups imab era (AIDS-Related Lymphoma International Prognostic of PTCL requiring different therapeutic approaches. Functional Index) has been developed with important participation of imaging has not yet impacted clinical management of PTCL; European groups. Similarly, an international effort has been further focus on advanced imaging metrics is needed. Advances made to define the prognostic factors of HL patients treated in circulating tumor DNA (ctDNA) technology offers real with ABVD and cART. opportunities both to advance understanding of disease biology Comparable survival between HIV-positive and HIV-negative through mutational profile analysis and to investigate the utility NHL and HL patients undergoing autologous peripheral blood of ctDNA as a dynamic biomarker. The therapeutic promise of stem cell transplantation was observed, leading to the conclu- CAR-T cell therapies demands investigation in PTCL. We look sion that, in the cART era, HIV-infected patients with lym- toward the very real possibility of rationally designed clinical phoma should be considered for autologous peripheral blood trials for molecularly defined PTCL subtypes, with therapeutic stem cell transplantation according to the same criteria adopted 11 Dreyling et al Research Roadmap: Malignant Lymphoid Diseases for HIV-negative lymphoma patients. The same could be applied inferior outcome.176 The IMWG frailty score was developed by for PTLD, but special caution should be taken for NRM, pri- which the level of frailty can be identified and which is associ- marily driven by infectious toxicity.163 ated with mortality and nonhematologic toxicity.175 Thereafter, the first clinical trials were designed for intermediate and frail Proposed research for the Roadmap patients.177,178 Biological research (1) To improve the knowledge of the mechanisms of lym- Proposed research for the Roadmap phomagenesis in immunosuppression-related lymphomas. (2) Minimal residual disease To evaluate the potential value of plasma load of gamma her- Before general introduction of MRD evaluation in daily pesviruses as a surrogate marker of residual disease in lym- clinical practice the optimal timing of MRD status has to be phomas in immunosuppressed patients. (3) To develop early defined. Confirming MRD status during therapy is fundamental, biological predictors of the development of lymphomas in because even MRD-negative patients can relapse, and sustained immunosuppressed patients. (4) To study the dynamics of the MRD negativity is strongly associated with better outcome.179 T-cell and natural killer (NK)-cell repertoire in immunosup- Furthermore, MRD-driven randomized clinical trials are needed pressed patients and its relationship with the development of to define the role of therapy intensification in MRD-positive lymphomas. patients or therapy discontinuation in patients with sustained MRD negativity. Several European initiatives are taken.180 Clinical research The value of peripheral blood mass spectrometry measure- (1) To develop pan-European clinical trials with the same ments should be explored, being more convenient for patients. new drugs used in nonimmunosuppressed patients, especially Preliminary data show concordant results between BM and in the setting of relapsed/refractory status. (2) To develop a PB MRD in 80% of patients with a similar prognostic value joint effort to conduct specific clinical trials for the treatment for PFS. Future studies will have to reveal whether PB MRD of infrequent subtypes of lymphoma arising in immunosup- can replace BM MRD or is complementary in predicting the pressed patients (eg, plasmablastic, peripheral T-cell, and pri- outcome.181 mary effusion lymphomas). (3) To conduct joint trials with therapies including antiviral agents, adoptive immunotherapy Next-generation T cell directing immune therapy (eg, genetically modified EBV-specific cytotoxic T cells), new The optimal timing of CAR-T cell and bispecific antibody drugs, monoclonal antibodies targeting cytokines, and CAR therapy needs to be defined. As primary and acquired resistance T cells.164 to T cell directing therapies occur, research on the optimal T-cell repertoire for effective killing and persistence of CAR-T cells Anticipated impact of the research is important. In addition, the role of tumor antigen downreg- The number of lymphomas arising in immunosuppressed ulation, the possibilities to increase tumor antigen expression patients is expected to increase, making it essential to initiate and the value of dual antigen targeting should be investigated. co-operative efforts to improve the knowledge of the mecha- Whether the myeloma immunosuppressive microenvironment nisms of lymphomagenesis and to develop more effective thera- can be overcome by the use of immunomodulatory drugs is pies (new drugs and immunologically based therapies), as occurs a research topic of interest both in vitro, as well as in clinical in nonimmunosuppressed patients. Progress in the knowledge of trials.172,182 the mechanisms of lymphoma development in these patients will Finally, it will be important to define how to choose between contribute to improving the treatment results and will hopefully CAR-T cell therapy and T-cell directing bispecific antibodies. help in the prevention of these lymphomas. Will this be guided by tumor or patient characteristics and severity of side effects? Will the current choice based on direct availability be overcome by access to allogeneic off-the-shelf MULTIPLE MYELOMA AND OTHER PLASMA CELL NEOPLASMS CAR-T cells.183 Will there be a possibility to control or cure the European research contributions disease with CAR-T cell therapy without any additional ther- Minimal residual disease apy? Is there a difference in cost-effectiveness? Bone marrow MRD, by multiparameter flow-cytometry/ next-generation flow and NGS, is a valuable long-term outcome High-risk disease predictor in MM.165 PET-CT imaging refines determination of The current definition of genetic high-risk needs revision. MRD negativity.166 There is disconcordance between PET-CT DNA sequencing will allow to detect all copy numbers vari- and NGS/multiparameter flow-cytometry in approximately ations, IGH translocations, and recurrent mutations allow- 35% of cases.167 Therefore, both BM- and imaging-based MRD ing multiparameter-based more precise risk assessment.184 are now implemented in the MM response criteria.168 With cur- Moreover, it is known that risk evolves over time, therefore, rent unprecedented lengths of PFS and OS, MRD is a valuable extensive molecular profiling should be performed longitudi- surrogate endpoint for PFS and OS, which would allow earlier nally in individual patients to get informed about the clonal registration and access to valuable treatment regimens. evolution and the prognostic impact of the different genetic profiles over time. In addition, it should be investigated Next-generation T-cell directing immune therapy whether novel immune therapies will be able to overcome the Recently, novel immune therapies, such as anti-BCMA negative impact of high-risk disease, which has until now only CAR-T cell therapies, improved both PFS and OS in end-stage been shown for double autologous transplant.174,185 Finally, the disease substantially. In addition, the bispecific BCMA-CD3, development of dedicated high-risk trials is important in order GPRC5D-CD3, and Fc-RH5-CD3 antibodies are promising to prevent underpowered sub-analyses of high-risk patients in approaches with encouraging responses rates.169–173 general randomized clinical trials. Such European initiatives are taken.186 Patients with unmet medical need There is still an unmet need for the treatment of patients with Frail high-risk disease based on molecular characteristics and frail There is currently no uniform definition of frailty in clini- patients.174,175 It was found that especially patients with a del cal practice. Additionally, the discriminative power of current (17p) clone size of >55% or those with bi-allelic disease har- scores is still insufficient to guide treatment decisions. Therefore, boring a mutation in the TP53 gene in the other allele have an further alignment and improvement of the frailty definition is of 12 (2022) 6:6 www.hemaspherejournal.com importance. It would be worthwhile to investigate the impact of Roche. BB is member of the advisory board, steering committee and expert functional geriatric assessments. Moreover, dedicated trials for for AbbVie, Miletyi, Novartis, Roche. CB received honoraria from Roche, frail patients are urgently needed.187,188 Janssen, BeiGene, Gilead, AbbVie, Celltrion, Pfizer, Novartis, Regeneron, Incyte; he received research funds from Roche, Janssen, AbbVie, MSD, Celltrion, Pfizer, Amgen. EC receives consulting fees from Illumina and Anticipated impact of the research AbbVie; he receives honoraria from EUSA Pharma, AstraZeneca; he is author Rational therapy approaches, concerning both the risk-based on a patent licensed to NanoString Technologies. BC receives honoraria from choice of therapy as well as response- driven modification of BMS, Gilead, Astra Zeneca. AD receives consulting fees from Roche, Acerta/ therapy, will be enabled by; AstraZeneca; he receives research support from Roche, Celgene/BMS, Kite/ Gilead, Incyte; he is advisory board member in Roche, Incyte, AstraZeneca, (a) refinement of the definition of high-risk molecular disease Genmab, Abbvie. FG receives consulting fees from Janssen, Amgen BMS/ and frailty improving the prognostic value Celgene, Sanofi, Pfizer, Oncopeptides, GSK, Roche, AbbVie; she receives hon- (b) addressing the value of novel treatment regimens in high- oraria from Janssen, Amgen, BMS/Celgene, Sanofi, GSK, AbbVie. PG receives risk patients by designing separate clinical trials, which consulting fees from AbbVie, AstraZeneca, ArQule/MSD, BeiGene, Celgene/ will providing more solid data in those patients Juno/BMS, Janssen, Lilly, MEI, Roche, Sanofi; he receives research support (c) increasing knowledge on the predictive value next to the from AbbVie, AstraZeneca, Janssen, Sunesis; he is an editor for HemaSphere. HG receives consulting fees from Amgen, BMS, Celgene, Chugai, Janssen, prognostic value of MRD measured by next-generation Sanofi; he receives research support from Amgen, BMS, Celgene, Chugai, flow/NGS and PET-CT Janssen, Incyte, Molecular Partners, Merck Sharp and Dohme (MSD), Sanofi, Optimization of next-generation immune therapy might lead Mundipharma GmbH, Takeda, Novartis; he is an advisory board member for Adaptive Biotechnology, Amgen, BMS, Celgene, Janssen, Sanofi, Takeda; to a cure for MM given the impressive results in heavily pre- he receives honoraria for Amgen, BMS, Celgene, Chugai, GlaxoSmithKline treated patients. (GSK), Janssen, Novartis, Sanofi. MJ receives research support from Abbvie, The proposed research road map will not only extend but AstraZeneca, Janssen, Roche; he receives honoraria from Janssen, Abbvie, also improve efficacy of the current treatment armamentarium. Genmab, Incyte. MJK received research support from Gilead; she receives Importantly, it will allow cost-effective treatment supporting a honoraria from Kite/Gilead, BMS/Celgene, Novartis, Miltenyi Biotec, Roche, proper use of health care resources and hopefully decreasing Takeda. BK receives honoraria for lectures from AAA, Ipsen, Novartis, MSD, global inequality in drug access due to the rising costs.189–191 Lilly and is an advisory board member for Ipsen. GL receives consulting fees from Roche, Gilead, Janssen, BMS, Novartis, AstraZeneca, Abbvie, Incyte, MorphoSys, Genmab, Karyopharm, Constellation; he receives research Summary box: Main research & policy priorities support from Roche, Gilead, Janssen, Bayer, AstraZeneca, MorphoSys; he receives honoraria from Roche, Gilead, Janssen, BMS, Novarts, AstraZeneca, • Establishment and fostering of pan-European scientific Abbvie, Incyte, MorphoSys. SL receives consulting fees from Genmab, Incyte, networks of both, basic science and clinical lymphoma Gilead, Orion, CHO Pharma USA, Novartis, Roche; she receives honoraria excellence from Novartis, GILEAD, Incyte. ALG receives consulting fees from Roche, • Further elucidation of molecular lymphopathogenesis to Gilead/Kite, Celgene, Novartis, Astra Zeneca, Abbie, Morphosis, Takeda; he identify predictive molecular markers as well as potential receives research support from Roche, Gilead/Kite, Celgene; he receives hon- targets for future tailored approaches oraria from Roche, Gilead/Kite. MVMM receives honoraria derived from • Strengthening of academic clinical trials (see also www. lectures and participation in advisory boards from Janssen, Celgene, Takeda, bureacracyincts.eu) Amgen, GSK, Abbvie, Pfizer, Regeneron, Adaptive, Roche, Seattle Genentech. • Partnering with patient advocacy groups to incorporate PM receives honoraria and is an advisory board member in Celgene/BMS, Janssen, Amgen, Sanofi, AbbVie. CM receives consulting fees from Abbvie, the foremost interests of our patients Janssen, AstraZeneca, Beigene; she receives research support from Abbvie • Most importantly, even opportunities for patients all over and Janssen. JO receives research support from Gilead Science and BeiGene; Europe to receive the optimal current standard of care she receives honoraria from Gilead Science. RO receives honoraria and is an advisory board member in BeiGene and Janssen. TR receives consulting fees from BeiGene, AstraZeneca, Janssen, Abbvie; he receives research support DISCLOSURES from BeiGene, AstraZeneza, Janssen, Octapharma, Moderna, GSK, Abbvie. MD receives research support from AbbVie, Bayer, Celgene, Janssen, KS receives research support from Janssen, Abbvie, Roche, AstraZeneca; he and Roche; he is a HemaSphere editor; he receives speakers honoraria from receives honoraria from Janssen, Abbvie, Roche, AstraZeneca. AT receives Amgen, Astra Zeneca, Bayer, Celgene, Gilead, Janssen, and Roche; and honoraria and is an advisory board member for Janssen Spa, Beigene, he belongs to the Scientific Advisory Board of Astra Zeneca, Bayer, BMS/ AstraZeneca, AbbVie. RUT receives payments for consultation and attending Celgene, Beigene, Genmab, Gilead, Incyte, Janssen, Novartis, and Roche. advisory board meetings from Atara. All the other authors have no conflicts MA is a consultant for Takeda, Bristol-Myers-Squibb, Karyopharm, Gilead, of interest to disclose. Incyte and receives research support from Roche, Johnson & Johnson, and Takeda. NG receives research support from Amgen, Pfizer, Novartis,Shire/ Servier, Jazz Pharmaceuticals, Incyte; she receives honoraria from Amgen, REFERENCES Celgene, Gilead, Novartis, Pfizer, Jazz Pharmaceuticals, Incyte. HT is a member of the advisory board for Roche, Celgene, Incyte. JG provides con- 1. Engert A, Balduini C, Brand A, et al. The European Hematology sultation for Abbvie, Astra Zeneca, BMS, Gilead, Janssen, Morphosys, TG Association Roadmap for European Hematology Research: a consensus Therapeutics; he receives research support from Astra Zeneca, Janssen and document. Haematologica. 2016;101:115–208. honoraria from Abbvie, BMS, Gilead, Janssen. AF is a member of advisory 2. Sant M, Allemani C, Tereanu C, et al. 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