The EHA Research Roadmap: Malignant Lymphoid Diseases

Abstract

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 coordinated 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. Malignant lymphoid diseases represent the most frequent hematologic malignancies, with an age-adjusted estimated incidence of 24.5 per 100,000 inhabitants in Europe,2 and are associated with significant mortality3 and morbidity. This disease group is highly heterogeneous in terms of frequency, epidemiology, biology, genetic abnormalities, and outcome. Although in a way all individual lymphoma subtypes may be characterized as rare diseases, some of them are relatively common, for example, multiple myeloma, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphomas (DLBCLs), follicular lymphomas (FLs), and Hodgkin lymphomas (HLs). Others are less common, for example, mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), T-cell lymphoma, and mucosa-associated lymphoid tissue (MALT) lymphoma, Waldenstrom’s Macroglobulinemia, or even very rare, for example, some subsets of marginal zone lymphomas (MZLs) and HIV-associated lymphoma. After the progress made in the morphological classification of these tumors in the 1990s, the advent of large-scale genomic approaches enabled identification of multiple molecular subsets, which may further subdivide the different entities in multiple rare diseases.4–6 These achievements justify the need for European-based epidemiological studies and contributions to the InterLymph consortium7 to investigate the role of environmental and lifestyle factors, which, in the context of inherited genetic background, may favor the development of these malignancies. Significant progress was also made in unraveling key biological features of these diseases, including (1) the more precise delineation 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 malignant cells and their microenvironment, which is especially critical in these diseases arising in lymphoid organs10; and (3) the emerging identification of constitutional genetic traits associated with an increased susceptibility to develop these malignancies.11,12 Although several European groups have already made outstanding contributions to this field, in part within large international consortia, further achievements will only be possible if major investments can be realized. These should particularly focus on establishing new cellular and animal models which are critically rare in the field of mature lymphoid malignancies to better understand how these diseases develop and for preclinical assessment of new therapeutic agents. Despite important advances in the past few years,13 the survival of patients with lymphoid malignancies remains unsatisfactory. This is true for the most aggressive malignancies (eg, ALLs, T-cell lymphomas, and some forms of DLBCL), which still are frequently fatal. In addition, the lack of cure in patients with multiple myeloma or indolent lymphoma is equally challenging. Furthermore, short- or long-term morbidities such as infertility, secondary malignancies, as well as cardiac, pulmonary, renal, or neurological dysfunction are associated with intensive treatment in HL or DLBCL. Chronic exposure to therapeutic agents such as in indolent lymphoma and CLL also represents a health burden for patients, as well as an increasingly relevant economic burden for the European Union.14,15 Attention to malignancies occurring in elderly patients should also be considered in this regard given the fact that life expectancies continue to grow. European co-operative groups have been leading clinical research in lymphoid malignancies in the past decades. Progress is being made in investigating the role of targeted agents in well-characterized molecular subsets. The number of new therapeutic agents under development in this field demands further academic research collaboration. For example, analyzing the medico-economic impacts of patient management should clarify the costs and benefits of novel therapeutic strategies, including those related to public health economics. These groups also need further support in their translational research activities, especially in their efforts to constitute and analyze large biobanks with high-quality clinical annotations. Efforts should also aim to eliminate the different outcomes observed in different parts of Europe and to improve patients’ survival and quality of life. HODGKIN LYMPHOMA Introduction Classical HL is a highly curable disease and for both localized and advanced-stage diseases, >90% of patients are alive 5 years after diagnosis. During their follow-up, however, a significant proportion of these young patients experience serious long-term toxicities related to the treatments of lymphoma. The reduction of long-term, treatment-related toxicities remains the goal of actual clinical trials. European research contributions Based on the seminal work of Gallamini et al,16 it appears that an early PET scan (e-PET) performed after 2–3 cycles of ABVD was able to segregate patients into two categories; early PET negative patients with an excellent prognosis and a possibility to reduce the amount of treatment; and early PET-positive patients with a worse prognosis suggesting no reduction but possibly intensification of treatment. In early stage HL, three European studies based on this approach were performed and published in the last 5 years.17–19 In early stage favorable HL, the objective was to avoid radiotherapy in e-PET negative patients. All three trials were not able to demonstrate the noninferiority of the no radiotherapy arm in terms of progression-free survival (PFS), but the overall survival (OS) was excellent and did not show any difference. Omission of radiotherapy is at the price of some reduction in tumor control and should be balanced with the expected individual risk associated with radiotherapy. In early stage intermediate/unfavorable disease, the same strategy was applied.18,20 In the HD17 study, noninferiority of the no radiotherapy arm was demonstrated and in the H10 study a 2.5% of difference of PFS was observed between the 2 arms suggesting that radiotherapy can be omitted in this situation. For e-PET-positive patients, only the H10 study evaluated early intensification of chemotherapy and demonstrated a better PFS with this strategy; improvement of OS was of borderline significance. In advanced-stage HL, three randomized studies evaluated reduction of the amount of treatment based on an e-PET evaluation.21–23 All these three studies were successful and demonstrated that a reduction of the amount of treatment given is possible when an e-PET negativity is reached after 2 cycles of chemotherapy. For e-PET negative patients, omission of Bleomycin, reduction to 4 cycles of escBEACOPP, or de-escalation to ABVD were validated by these three trials. In adolescents and young adults (AYA), to limit gonadal damage and second malignancies, the European trial EuroNet PHL C124 lead to the replacement of procarbazine with dacarbazine and to restriction of RT indications to patients with an adequate response after 2 first cycles of OEPA. EuroNet PHL C2 explores moderate treatment intensification in order to further limit RT indications. Finally, the incorporation of Brentuximab Vedotin (BV) and checkpoint inhibitors in the ABVD regimen was evaluated recently. Two European studies25,26 showed that replacing 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 Individualization of treatment should be pursued in the context of PET-adapted therapy. Besides early PET negativity, total metabolic tumor volume appears to be an important prognostic factor and should be tested for better tailoring the risk-adapted treatment strategy. Another possible important avenue for future research is the detection of tumor DNA in the blood of the patients. Its potential use to identify some baseline prognostic factors, monitor treatment, and detect early relapses warrant future development. In this context, systematic banking of tumor and plasma samples, such as PET images is recommended in future European trials. BV and checkpoints inhibitors have a definitive place in refractory/relapsed HL lymphoma, their possible integration into first line for selected patients need still to be demonstrated in future phase III trials. Anticipated impact of the research Reducing toxicities and possibly improving the high-cure rate will remain the goal of our future strategies and probably led to even more individualized therapy, incorporating PET, cell-free DNA, and possibly new drugs. As the costs of these new tools are elevated, they will probably not apply to each patient and be restricted to a subset of HL. Special attention should be given to the dissemination of these expensive innovations (and future ones such as CART-T cells) in all countries in Europe. ACUTE LYMPHOBLASTIC LEUKEMIA Introduction Acute lymphoblastic leukemia is a life-threatening disease affecting children and adults. Treatment consists of combination chemotherapy, with allogeneic hematopoietic stem cell transplantation (HSCT) restricted to high-risk or relapsed ALL. Five-year event-free survival is correlated to age and in contemporary treatment, protocols reach over 80% for children and 40%–70% for adults, due to the increased incidence of poor prognostic features and lower tolerability of intensive chemotherapy in older patients.1 European research contributions The treatment of ALL in Europe is undertaken by national study groups and international consortia such as BFM/AEIOP and ALL-Together for children and EWALL for adults. National study group clinical databases, reference laboratories, or associated biobanks are essential for research on disease biology and prognostication and are sources of reliable real-world data. European standardization for monitoring of minimal residual disease (MRD) by the EuroMRD/ESLHO group made risk-based individual treatment modification possible. As a basis for intergroup trials, consensus definitions for adverse events and treatment response have been developed for pediatric ALL.27,28 Gene expression profiling and sequencing have identified many new subtypes of B-cell precursor (BCP) and T-cell lineage ALL; their number has complicated both European standardization and risk-based personalized therapy. Immune therapies with bispecific antibodies and conjugated antibodies for BCP-ALL have replaced standard of care chemotherapy in R/R ALL,29 led for the first time to marketing authorization for MRD-positive ALL30 and are increasingly being tested in first-line trials. CAR-T cell products became available within clinical trials and with the marketed product for patients younger than 25 years. Further trials are directed to the clinical evaluation of inhibitors directed to BCR-ABL-like or JAK-class fusion-gene subgroups.31 On the other hand, the clinical impact of intensive conventional treatments like HSCT with TBI-based conditioning has been underlined.32 Proposed research for the Roadmap Evaluation of the prognostic impact of the myriad oncogenic subgroups in modern, MRD-risk stratified, treatment protocols is challenging. It is essential, in addition to identifying and unraveling potential prognostic lesions, to increasingly focus on functional studies addressing tumor dependency of new lesions (including those found in subclones) in relevant models. In vitro testing strategies to select compounds for individual refractory patients are emerging33 and require European concertation and adaptation of data management, clinical trial design, and drug accessibility circuits. Epigenetic landscapes are more accessible for the identification of actionable targets, such as hypomethylating agents34 and multiparameter prognostic scores will increasingly combine clinical and molecular features.35 Our knowledge about the supportive (and protective) role of the bone marrow microenvironment should also be expanded.1 It is also essential to address future ALL classification, which needs to integrate molecular oncogenic characteristics and next-generation MRD and requires standardization of the optimal diagnostic standards. Late effects of treatment, such as osteonecrosis,36 are increasingly relevant with improved ALL survival, requiring joint efforts of pediatric and adult study groups to better understand biology, improve surveillance and define potential treatment modifications. Age is one of the most important prognostic factors for ALL. Uncertainty persists on which types of pediatric-based therapies are tolerated in different age groups so, at least, clear reporting standards are necessary. The development of innovative treatment strategies for older patients can help younger patients and vice versa. Increasing regulatory issues are emerging regarding drug development, marketing authorization, and reimbursement for new drugs in adult ALL, which are treated with complex combination therapies and management strategies. Support structures developed for pediatric ALL1 should be extended to adult ALL, in collaboration between national competent authorities, Institutional Review Boards, pharmaceutical companies, and academic study groups. The evaluation of new compounds in rare molecular subgroups of ALL will require European-level collaboration with the European Medical Agency and intergroup data-sharing, as in the Harmony IMI initiative, https://www.harmony-alliance.eu. New strategies for clinical trial design must be developed in concertation with patient representatives, and there is an urgent need to support the successful infrastructure of European academic multicenter study groups through funding programs. In the next years, these challenges will become evident for the integration of new monoclonal antibodies and cell therapies into first line. Several clinical trials are ongoing in Europe and worldwide requiring harmonization to enable future meta-analyses.37–39 The scientific questions do not only focus on the impact of a single compound but new combination strategies and the role of current drugs, risk stratifications, and approaches like HSCT. One major research question will certainly focus on the future role of HSCT in adult and pediatric ALL. For Ph+ ALL the selection of TKIs, the efficacy of chemotherapy-free regimens,40 indications for change of TKI, the impact of MRD measured with different methods, the role of immunotherapies, and HSCT will be important research questions. One priority for the research agenda is the management of T-ALL and T-LL. Less progress has been made regarding the biologic characterization and prognostic classification, with a relative paucity of promising new compounds41 and immunotherapeutic targets. Whereas the overall prognosis of T-ALL is quite favorable, new approaches are urgently required for poor prognostic subgroups since survival after relapse is rare. Anticipated impact of the research Future treatment will still be based on current very successful standards, however, targeted therapies including immunotherapies will be increasingly implemented. These should improve the prognosis of high-risk patients but also significantly reduce treatment-related morbidity for patients of all ages, and especially for long-term survivors of childhood ALL. In addition, individualized drug dosing may prevent underdosing and hence may reduce the risk of relapse, while preventing over-dosing and associated toxic side effects. DIFFUSE LARGE B-CELL LYMPHOMA AND BURKITT LYMPHOMA Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common clinically aggressive lymphoid neoplasm. In addition to the most common DLBCL “not otherwise specified” type, comprising germinal center B-cell, activated B-cell like subtypes, the 2016 WHO classification recognizes specific variants (eg, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive DLBCL) and high-grade B-cell lymphoma with MYC and BCL2 or BCL6 translocations as a separate entity (Figure 1).42Figure 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 lymphomas; 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.European research contributions European researchers have contributed to international efforts redefining molecular classifications of aggressive B-cell lymphoma beyond the transcriptionally cell of origin classification to identify genetically defined subtypes that suggest a specific lymphomagenesis, corresponding to a distinct outcome and allowing to consider different treatment approaches.43,44 Additionally, European hematologists participated in major clinical trials aiming at improving first-line treatment of DLBCL.45–47Until now, however, intensification of treatment, the addition of maintenance therapy, the introduction of immunomodulatory or novel-targeted agents have neither improved outcomes in unselected patient populations nor identified selected subgroups of patients, who could benefit from a new combination. On the other side, these studies have been able to reduce toxicity without affecting efficacy in patients at low-risk48 and new initiatives have been proposed to guide treatment strategy based on early response, particularly based on PET-CT.49,50 In addition, several European studies evaluated new agents or new combinations.51–55 The development of CAR-T cell therapy in relapsed and refractory DLBCL was a revolution initiated in the United States, but the networking of European treatment centers has made it possible to observe a large number of patients and continue to evaluate this method in real life. In AYA, DLBCL is the second most common aggressive B-NHL. Outcome for DLBCL patients improved in recent clinical trials using Bukitt-type treatment regimen.56 Analogue to adults, genetic sub-classification will support subgroup identification and treatment modulation.57 Proposed research for the Roadmap The Roadmap is in line with the one proposed five years ago. We have now tools that will allow to further investigate mechanisms of DLBCL pathogenesis including novel models and leverage high-throughput functional screens (genetic and pharmacological) to identify unappreciated vulnerabilities and guide future drug development. Recent advances in understanding of the genetic heterogeneity of DLBCL that led to the definition of molecular subgroups could be accessible to existing or newly designed targeted therapies. The ability to recognize these subgroups in a reliable, reproducible but also timely manner will be an important challenge to introduce these drugs in the first-line treatment in AYA. The availability of circulating tumor DNA (ctDNA) could help to characterize the genomic profile of the disease. The next wave of technologies will allow to capture single cell and spatial heterogeneity and to comprehensively understand the role of the tumor microenvironment and the “fitness” of the immune system. The knowledge of the immunological synapse will be invaluable to better address treatment with immunomodulatory drugs, bispecific antibodies, and CAR-T cells. These data should allow the construction of a new prognostic indices integrating multiomics and clinical characteristics. It will be of interest to monitor early treatment response to guide subsequent treatment, either in the direction of a reduction or toward a different strategy. The combined use of PET-CT and ctDNA will be key tools for this longitudinal assessment. The disappointing results of large studies aiming to improve first-line treatment and the detected genetic and clinical heterogeneity of DLBCL underline the limit of “one size fits all” in this disease. Tailoring therapeutic approaches of specific clinical, morphological, and molecular entities will require collaboration of European national co-operative groups and evolution of the methodology how clinical trials are performed. Similarly, real-life studies, based on the observation of a large number of patients, will be very useful in the evaluation of new treatments, especially those that are very expensive. Anticipated impact of the research These research directions aim at a better understanding of biology and a better management of patients with DLBCL. The personalized treatment, more effective and safer, for DLBCL patients is not yet in our hands. A close collaboration between investigators, academic researchers, pharmaceutical companies, and patient associations will be necessary to achieve this goal and allow this progress to be shared throughout Europe. MANTLE CELL LYMPHOMA Introduction Mantle cell lymphoma represents approximately 7% of all non-Hodgkin lymphomas (NHLs) and is characterized by the translocation t(11;14)(q13;q32) and the overexpression of CCND1 (Figure 2). From a tumor biology perspective, two molecular subtypes can be defined; the conventional, nodal type, typically characterized by aggressive clinical course and requiring immediate treatment, and the non-nodal, often leukemic type, with more indolent clinical behavior. The standard approach for younger patients is based on immunochemotherapy, which consists of rituximab and CHOP-like or high-dose Ara-C–containing regimens followed by high-dose treatment with autologous stem cell transplantation (ASCT) and rituximab maintenance. Elderly patients are usually treated with rituximab and CHOP (R-CHOP) or R-bendamustine, followed by rituximab. During the last 5 years, several novel agents have been introduced and approved for the treatment of relapsed and refractory MCL; the immunomodulatory agent lenalidomide, the BTK inhibitor ibrutinib, the BCL2 inhibitor venetoclax, and most recently, brexucabtagene autoleucel, a CAR-T cell product. Many other agents are undergoing clinical development in MCL, including newer generations of BTK inhibitors, bispecific T-cell engagers, and antibody drug conjugates.58Figure 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.European research contributions During the last 5 years, European co-operative groups have contributed significantly to the development of treatment strategies for the young as well as the elderly MCL population. In the French LyMa trial, rituximab maintenance post ASCT has been shown to prolong overall survival in the first-line setting, a finding now implemented as standard practice.59 A few trials have also explored the use of lenalidomide maintenance. In a phase 3 trial by the Italian FIL group, lenalidomide post ASCT was shown to improve PFS,60 and in the 2nd European MCL Network Elderly trial, the addition of lenalidomide to rituximab maintenance (R2) prolonged PFS compared with rituximab alone.61 European groups have also explored the use of BTK and BCL2 inhibitors in untreated patients with MCL, such as the combination of rituximab and ibrutinib (IR) in low-risk MCL by the Spanish group,62 and the addition of venetoclax consolidation after R-BAC63 in elderly high-risk MCL. Moreover, a number of novel combinations have undergone study in relapsed/refractory MCL among co-operative groups in Europe, including temsirolimus, an mTOR inhibitor, in combination with R-bendamustine,64 ibrutinib-R2,65 venetoclax-R2,66 as well as obinutuzumab in combination with venetoclax and ibrutinib.67 Furthermore, European groups have been instrumental in the identification of the molecular biology and genome and epigenomic alterations of MCL subtypes68 and specific molecular high-risk groups of patients, particularly defined by the presence of mutations of TP53, but also other genetic aberrations, including KMT2D mutations and CDKN2A deletions.69–71 Proposed research for the Roadmap A number of phase 3 trials, with potential to change clinical practice in untreated patients with MCL, are ongoing in Europe. These include the TRIANGLE trial, assessing the impact of addition of ibrutinib in induction and maintenance, as well as challenging the use of ASCT72; the European MCL Network Elderly R2 trial, evaluating the addition of cytarabine to standard R-CHOP induction; and the ENRICH trial, comparing a chemo-free regimen, ibrutinib-rituximab, to standard chemoimmunotherapy in elderly patients. Taking this one step further, ibrutinib-rituximab is compared with venetoclax- ibrutinib-rituximab in a randomized phase 2 trial, the OASIS II. Finally, a randomized trial will compare this triple combination to a chemotherapy standard (MCL elderly III). Other venues of development include ambitions to develop response adapted treatment strategies, based on MRD66; incorporation of the new knowledge emerging from biology studies into risk-based strategies, specifically targeting biological high-risk populations such as TP53-mutated MCL; strategies to improve outcome for BTKi-refractory disease; as well as real-world evidence studies, based on the high quality, nation-wide registers present in many European countries. Anticipated impact of the research Mantle cell lymphoma is a rare lymphoma subtype but also a disease where there is an abundance of novel agents with high activity. We expect that incorporation of novel-targeted agents in front-line combinations ultimately will lead to improvement in survival, and possibly even cure, while reducing early and late side effects. FOLLICULAR LYMPHOMA Introduction Follicular lymphoma is the second most common lymphoma, with the highest and increasing incidence in Europe (approximately 3.14 cases per 100,000 persons per year).73 FL represents a heterogeneous disease both clinically and biologically. The chromosomal translocation t(14;18) and recurrent alterations in epigenetic regulators are pivotal genetic hallmarks. FL primarily affecting older adults, the disease is characterized by a variable clinical course spanning from those patients exhibiting an indolent behavior to high-risk patients with shortened survival such as those who progress within 24 months of initial immunochemotherapy (POD24) or undergo histological transformation. Guidelines for the diagnosis and treatment of FL were outlined recently by the European Society for Medical Oncology.74 There is no consensus on standard of care particularly for relapsed disease, but there is increased interest in novel-targeted agents and immunotherapeutic approaches. European research contributions European groups have led the way on both the biological and therapy front. Major contributions to unraveling the pathogenesis of include better understanding of the premalignant dynamics of FL development, detailed description of the genetic landscape of FL, the contribution of nongenetic determinants such as the microenvironment and the complexity of genetic heterogeneity and evolution. Emerging data demonstrate that mutations present in tumor cells are implicated in phenotypic and functional remodeling of the FL microenvironment, favoring immune escape mechanisms, and providing a favorable niche for FL cell survival. Furthermore, the adoption of single-cell technological approaches illustrate that the continuum of B-cell states are broader than the traditional germinal center cell of origin of FL. 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 widespread use of immunochemotherapy78 and introduction of novel monoclonal antibodies,79 resulting in improvement in survival with median overall survival for FL now 15–20 years. More recent trials have focused on chemotherapy-free regimes targeting the FL cells and the tumor microenvironment leading to the first approval of the immunomo