Tackling Mantle Cell Lymphoma in Europe

Abstract

An expert panel convened by the European Alliance for Personalized Medicine (EAPM) reflected on achievements and outstanding challenges in Europe in mantle cell lymphoma (MCL). Through the prism of member state experience, the panel noted advances in outcomes over the last decade, but highlighted issues constituting barriers to better care. The list notably included availability of newer treatments, infrastructure and funding for related testing, and shortages of relevant skills and of research support. The prospect of improvements was held to reside in closer coordination and cooperation within and between individual countries, and in changes in policy and scale of investment at both national and EU levels.

1. Introduction

Mantle cell lymphoma (MCL) is a hematological malignant disease composed of 2.5–6% non-Hodgkin’s lymphomas. The treatment has evolved over time, and different treatment options exist for patients with aggressive variants depending on age, performance status, and possibility of bone marrow transplant [1,2,3]. There are over 70 subtypes of lymphomas, with different diagnostic evaluation, different treatment protocols, and different outcomes. Lymphoma subtypes are often categorized into three major groups: chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL). Out of NHL, MCL is a very rare cancer of the B lymphocytes (B cells) [4,5]. This subtype of lymphoma is usually fast-growing, but it can also behave more indolently (slow-growing) in some patients [6]. Numerous advances in the understanding of the biology of MCL have been achieved over the years and consequently, there has been a rise in treatments and clinical trials with targeted therapies [7].

What can make tackling MCL more effective in Europe—and what makes it harder? Those are the questions addressed by an expert panel assembled by European Alliance for Personalized Medicine (EAPM) in early 2022, in a bid to improve the situation for patients at member state and EU level. Possibilities of successful treatment are improving, but there are still high unmet needs for patients including limited treatment options, wide variations in treatment regimens, availability, and continuing uncertainty over their use [8,9]. While research continues to illuminate the options, it can be impeded by lack of funding, as well as fragmentation of effort and deficiencies in the necessary infrastructure.

The discussions revealed that the challenges—including late or incorrect diagnosis, lack of access to appropriate therapies and expertise, lack of commercial feasibility in developing new therapies, difficulties in conducting well-powered clinical studies, and the paucity of tissue banks—could be meaningfully assessed by breaking them down into supply-side and demand-side issues. The demand side was seen as primarily influenced by governance, clinical standardization, awareness, and education, while the actual supply is influenced predominantly by equitable reimbursement, infrastructure for conducting and validating tests, and testing access driven by evidence generation. The principal conclusions to emerge included the desirability of linking national efforts by those engaged in care and promoting a European approach to reinforce improvements. Some of the gaps identified might, it was argued, be filled by assistance from the EU level, where current major policy initiatives offer direct or indirect opportunities. At the heart of the discussions was the need to find ways of persuading policy makers to support improved diagnosis and treatment of MCL patients. The picture drawn by the expert panel is of opportunities currently being missed, and potential unfulfilled. However, at the same time, there were ample suggestions of pathways towards seizing the opportunities and realizing the potential.

2. Situation Report

The current panorama of MCL care and research in Europe is exemplified by the reports and comments of experts at an EAPM panel in April 2022.

The picture of gaps in both demand and supply is unsatisfactory for patients, for clinicians, and for the future of effective therapy. Despite progress in treatment options, particularly in the last decade, MCL remains a disease with a high number of relapses and a poor long-term survival for many patients [9,10,11,12]. Though rare, it is an aggressive disease [13]. Although MCL generally responds to initial treatment, the disease inevitably relapses, and median overall survival following initial induction therapy is 3–5 years and exhibits varied clinical behavior and prognoses, reflecting the biologic heterogeneity of the disease [14,15,16,17]. Many recommendations regarding use of chemoimmunotherapy to treat relapsed/refractory MCL are based on limited studies and few randomized comparative trials [18]. Elucidation of the molecular pathophysiology of MCL has resulted in new and specifically targeted agents as alternatives to combination chemoimmunotherapy at diagnosis [19]. There are now possibilities to stratify patients as low, intermediate, or high risk [20]. However, although multiple treatment options are available as novel monotherapies for relapsed/refractory MCL, no clear standard of care is recognized in EU or US treatment guidelines [3,14]. Differences persist in the guidelines for induction therapy issued in the US and in Europe, and in recommended treatment regimens. Molecular-based agents together with chemoimmunotherapy may be appropriate for some patients but potential toxicity needs to be taken into consideration. Treatments differ with regards to efficacy, adverse event profiles and mode of administration, and the choice of treatment is also dependent on factors such as patient fitness and wishes [5,10,21]. The Mantle Cell Lymphoma International Prognostic Index (MIPI), the first prognostic index for MCL patients, is based on independent prognostic factors including age, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase (LDH) level, and leucocyte count. On the other hand, Ki-67 staining by immunohistochemistry, which identifies proliferating cells, has showed strong prognostic relevance in MCL both alone and when combined with the MIPI [22]. A study conducted by the European MCL Network confirmed that the NanoString platform-based MCL35 assay is a reliable prognostic biomarker in MCL patients which identifies subgroups with different outcomes via a proliferation signature-based score [23]. Specialists have an important role, as in all rare cancers, to identify patients early and assess the most appropriate treatment based on clinical characteristics and personal choice of each patient [7,24,25].

Globally, incidence of NHL has increased while mortality and its annual percentage change have remained relatively stable [26]. According to the Munich Cancer Registry in Germany, for the period 2007–2020, average mortality of patients with MCL was 0.7/100,000 WS, N = 249 for males while for females it was 0.2/100,000 WS N = 111 [27]. In France, it was shown that when comparing patients with MCL included in clinical trials or registered in cancer registries, patients from clinical trials were younger and had a less advanced stage. An excessive mortality was seen mainly in elderly MCL patients from registries, confirming patient selection bias in clinical trials [28]. A Spanish study which involved 177 lymphoma patients with COVID-19 infection showed an overall mortality rate of 34.5% after a median follow up of 27 days. Significant predictors of death were the active disease and age ≥70 years [29]. In the USA, for comparison, 8755 patients were diagnosed with MCL between 2000 and 2013. Incidence (MCL cases/100,000 persons) increased from 0.711 in 2000–2006 to 0.800 in 2007–2013 (p < 0.001), and was significant among older male and female patients ≥ 65 years, and among non-Hispanic Whites and Hispanics, but not among those aged <65 years and non-Hispanic Blacks [30,31].

Research continues, focused particularly on relapsed and high-risk patients. There are different treatment options for younger patients without comorbidities and for elderly fit patients [32]. High-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients has shown benefits, as has maintenance rituximab and bendamustine in older patients. Allogeneic stem cell transplant represents a potentially curative option for younger patients, but guidelines in 2017 stated that there were insufficient data to support this in front-line treatment [8,9,33]. The inclusion of ibrutinib, lenalidomide, and bortezomib represents an important advance for patients ineligible for, unable to tolerate, or failing high-intensity combination chemotherapy. However, effective therapy for patients with relapsed MCL with ibrutinib resistance, aggressive form of the disease, and/or transplant ineligible patients represents an important unmet medical need [8,34]. Minimal residual disease (MRD) has been increasingly investigated in MCL [35]. The potentially valuable use of MRD as a surrogate end point for progression-free survival in comparing the efficacy of different treatments in randomized trials is also still hampered by limitations in take-up in clinical routine, partly because of the need for patient-specific primers and standardization [36]. In contrast to real-time quantitative polymerase chain reaction (qPCR) of immunoglobulin heavy chain (IGH) or BCL1-IGH clonal markers, droplet digital PCR (ddPCR) allows absolute quantification of MRD samples. The European MCL network evaluates the prognostic significance of ddPCR in the context of prospective trials [37].

The value of the wider range of treatment options is not to be underestimated, but their optimal use requires fulfilment of a series of complementary conditions in testing, infrastructure, and training in advanced techniques. There is a need for a better understanding of how to incorporate novel therapies and utilization of risk-adapted treatment approaches together with a high unmet need for effective treatments, particularly for relapsed/refractory MCL and for elderly and frail patients [8,38]. The use of autologous anti-CD-19 CAR-T cell therapy, first authorized in Europe in 2020 [39], requires careful work-up of the patient, an experienced interdisciplinary team, and a specialized hospital with follow-up resources, as well as agreement on the balance of quality and efficiency, cost, access, and expertise to successfully implement this technology in healthcare [8,14,40]. Another challenge is that centers providing cellular therapy need a robust clinical infrastructure to handle the complex scheduling logistics, maintain the “chain-of-custody” and “chain-of-identity” of the cellular product, and facilitate communication to manage potentially severe toxicities. High costs can be associated with managing adverse events occurring during treatment. There is also a great need for highly qualified personnel and experienced clinical and non-clinical staff at the center [41]. The introduction of personalized medicine into clinical practice would permit a more precise response to the biological and clinical heterogeneity of MCL. However, that in turn also requires reliable prognostic tools [42,43,44,45].

Common Problems through National Perspectives

The situation across Europe varies widely from country to country in terms of governance, clinical standardization, awareness and education, provisions for reimbursement, infrastructure, and evidence generation, although the challenges presented by MCL are similar everywhere. There is a lack of availability of modern diagnostic techniques—including p53 sequencing—and of novel treatments that have been approved by EMA, but remain restricted, often accessible only through clinical trials, and reimbursement for maintenance therapy is hard to obtain in some countries. Challenges in terms of infrastructure include deficient or absent biobanking of blood and marrow for MCL patients, limited availability of population-based data or information on local treatment patterns and outcome, and absence of reliable validated tools to assess mutational status.

This report provides a snapshot of varying conditions in a large sample of European countries represented and reported on in the EAPM expert panel, broken down into the broad categories of demand and supply. The categories are by nature somewhat arbitrary, and the data do not always fit precisely the sub-categories, but it offers an overview of some of the principal challenges in each country (see Appendix B).

3. Demand

3.1. Governance

Given the challenges posed by MCL as a very rare cancer, with patients often presenting very aggressive forms of the disease, it would be important for these patients to benefit from the expertise of multidisciplinary teams as the model provided for by the European Reference networks. These have a vital role in developing understanding, diagnosis, and treatment of rare cancers, and their unique capacity to mobilize expertise across Europe through virtual collaboration is realizing much of what has been previously a scattered and therefore under-exploited asset. Moreover, given the variety of lymphoma subtypes, it is crucial to encourage the collection of clinical data on each sub-type of rare and ultra-rare cancers. However, there are continuing national variations in practice over prescribing, organization of registries and of hematological and transplant centers, and attention to determinants or potential risk factors [45]. The Lymphoma Study Association (LYSA) is an independent network dedicated to clinical lymphoma research projects, frequently in collaboration with international scientific teams. Its clinical studies range from first-in-man tests of new treatments to the establishment of reference therapeutic strategies [46]. The European MCL Network of 15 national lymphoma study groups complemented by experts in histopathology and molecular genetics established two standard treatments. For younger patients, it was Ara-C containing induction followed by Ara-C containing myeloablative consolidation with autologous stem cell rescue and rituximab maintenance. For elderly MCL patients, it was R-CHOP induction followed by rituximab maintenance [47] (see Appendix A).

3.2. Clinical Standardization

There are different treatment options for patients with MCL, but most patients will start with chemoimmunotherapy. Stem cell transplants and radiation therapy are sometimes used in combination with chemoimmunotherapy. Additionally, CAR T-cell therapy was recently approved by the FDA for patients who have not responded to or have relapsed following treatment. With ongoing clinical trials, there is a great promise for new advancements [48]. Guidelines and recommendations have emerged at national and at European level, but sporadically rather than systematically, and they are not always followed, with national practices continuing to vary in implementing important biological risk factors in the clinical routine, treatment efficacy varies depending on histological lymphoma subtypes, and knowledge of factors associated with response to treatment or survival is currently still limited [45]. Consensus has yet to be reached regarding use of biomarkers for therapeutic decision-making in real-life settings (see Appendix A).

3.3. Awareness and Education

When first diagnosed with MCL, 30% of respondents did not understand the characteristics of their subtype. Furthermore, when it came to understanding side effects, 21% did not understand and the number was even higher (27%) of those who did not understand how to manage those side effects. These numbers prove the value of better communication between doctors and patients. Both healthcare providers and patients need to be aware that active communication is a key element during the treatment process, even more given the nature of MCL progression and the relapse rates [7]. Studies suggest that communication between peers and evidence-based and regularly updated national recommendations can significantly improve the outcomes of patients with lymphomas, even without the broad use of new expensive agents, and there is an appetite for collaboration and development of common standards, manifested for instance in regular meetings among regional experts in some countries (see Appendix A).

4. Supply

4.1. Reimbursement

MCL is one of the most aggressive lymphomas and can lead to poor patient outcomes. While targeted therapies are approved for MCL, reimbursement in many countries is still lacking or not provided for all components in the treatment regimen. With financial concerns being one of the top barriers to treatment, these patients may be confined to conventional therapies [7]. There is a split between hospital and other healthcare budgets—for basic or specialized drugs or transplant procedures—and distinct rules on prescribing authority or drugs from a list of expensive drugs for strictly defined indications. Physicians in some countries can administer drugs outside of the reimbursable list only with the agreement of hospital drug boards and management, and in others, there are strict limits and frequent delays on reimbursement of many newer therapies (see Appendix A).

4.2. Infrastructure

There have been many advances in understanding the biology of MCL, but centers that provide cellular therapy require a robust clinical infrastructure, and this poses a great challenge. Moreover, highly qualified personnel and experienced clinical and non-clinical staff are needed in centers [8]. There is a lack of adequate tissue banks for MCL, often owing to lack of dedicated funds and staff, and the absence of binding regulation, limited availability of advanced laboratories and more complicated molecular testing techniques such as p53 sequencing, and a lack of biobanks (see Appendix A).

4.3. Evidence Generation

MCL is one of the most aggressive lymphomas and can lead to poor patient outcomes. Subtype reporting can be effective in providing specific unmet needs of patients with MCL [7]. However, countries suffer from insufficient provision for independent clinical studies, because of complicated bureaucracy and the lack of study infrastructure, the legislation covering biobanking and rules about contracting, and difficulties in obtaining new drugs, as well as human resources and laboratory logistics, and cost obstacles. Trials in early phases tend to be conducted more in the US, which is preferred due to the speed of approval there (see Appendix A).

5. Discussion

The availability of hematology centers varies, as does the existence of national treatment guidelines and recommendations, and specific issues such as consensus regarding use of biomarkers for therapeutic decisions. What is often encountered when clinical studies with CART therapy are set up is the lack of referral networks/mechanism between centers with infrastructure for CART and those without. Effective networking could help improving outcomes and this could be incentivized by the healthcare systems. Despite the differences from country to country, what also emerges is a range of common features.

However, some of the common features reported offer a more optimistic perspective. There are numerous examples of national networks for diagnosis, treatment, or research, and frequent expressions of interest from clinicians and academics in alignment and cooperation—including at European level. A Croatian comparative study suggested communication between peers and evidence-based and regularly updated national recommendations can significantly improve the outcomes of patients with lymphomas, even without the broad use of new expensive agents [49]. The leading Spanish network of treatment centers ensures regular contacts and comparisons across the country. At European level, the ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up for MCL released in mid-2017 in accordance with the ESMO standard operating procedures for Clinical Practice Guidelines development was recently endorsed by the EHA Lymphoma Working Group (LyG) as a leading example of this form of collaboration [50].

The evident enthusiasm for better and more detailed diagnosis and treatment could find another outlet in pursuing further opportunities at the European level. Funding programs exist for actions addressing cancer—such as EU4Health, which published two waves of calls in 2021, leading to 16 major initiatives. The Work Program for 2022 was recently adopted and included again a significant number of actions addressing cancer, this time with a strong focus on prevention and diagnosis [51]. The EU’s Beating Cancer Plan is now coming on-stream, offering the possibility to shape its attention—and funding—to MCL. The evolving Cancer Mission also provides a chance to influence the EU’s strategic approach to different forms of cancer. The European Health Data Space proposed in early April 2022 aims to facilitate the data exchange among healthcare professionals, researchers, and innovators, and will offer funding for strengthening national as well as European data infrastructures [52]. In addition, the current plans for a revision of the EU’s general pharmaceutical legislation and the ongoing implementation of the EU’s recently adopted Health Technology Assessment regulation are opening up the discussion of access to new medicines in ways that could prove beneficial to all types of cancer. The key to any successful strategy at European level is mobilizing the maximum degree of national synergy in advance, so as to maximize the impact of messages delivered into the European decision-making arena.

6. Conclusions

While the optimal diagnosis and treatment of MCL is still disparate in Europe among population groups and between countries, a clearer identification of the gaps can help to plan continued improvements, at national and at European level. The awareness of the current deficiencies, coupled with the growing evidence of a will for a more coordinated and better-aligned approach, provides grounds for generating a common approach to policymakers at national and European level in order to obtain better support for the investment and services for physicians, researchers, and ultimately, patients.