Resumen de Introduction to the symposium ‘Targeted therapy in B-cell malignancies’
The treatment of lymphoproliferative malignancies is going through a paradigmatic change from traditional chemotherapy-based schemes to targeted biological approaches. This development builds upon recent systematic research and discoveries of key pathways that are deregulated in B-cell malignancies. The development of new targeted therapies, most notably revolving around B-cell receptor signalling, has opened up for personalized treatment and management and promises to substantially improve the prognosis and survival as well as the quality of life of the patients diagnosed with these malignancies. Although with a common origin from mature lymphoid cells, the molecular biology of this disease group is strikingly varied and the clinical course ranges from decades of chronic indolent disease to acutely life-threatening symptoms, underscoring the need for tailored approaches. Journal of Internal Medicine arranged a 2-day symposium in Stockholm entitled ‘Targeted therapy in B-cell malignancies’ with the purpose to bring together basic and clinical experts to discuss the current status and future directions in this rapidly evolving field. After the conference, the invited speakers were asked to prepare four state-of-the-art reviews that are briefly introduced below and published in this issue.
Lymphoproliferative malignancies, including mainly B-cell neoplasms (90%), together rank amongst the 10 most common cancer forms in the Western World. Overall, the incidence is highest in the USA and Canada and lowest in some Asian countries including Thailand and China [1]. The incidence is also generally but not invariably higher amongst men compared to women. In spite of these differences and a dramatic rise in incidence during the latter half of the 20th century, as summarized in the first review by Smedby et al., the causes of this group of malignancies are still incompletely understood. Well-established risk factors include states of severe immune suppression such as HIV/AIDS or medication following organ transplantation. More recently, knowledge has been gained around the roles of chronic immune stimulation and certain infections. In addition, the genetic susceptibility of major subtypes of B-cell malignancies has been unravelled through collaborative consortia, pointing to an additional role for variations in inherited immune function [1].
In line with the epidemiological evidence of associations between diseases of immune perturbation and risk of B-cell malignancy subtypes, studies of the clone-specific B-cell receptor immunoglobulins imply a pivotal role for B-cell receptor stimulation in the development of several indolent B-cell lymphoma subtypes [2]. As highlighted in the second review by Ghia et al., these findings further indicate that chromosomal aberrations are not the only steps of importance for malignant transformation but also that surrounding cells in the tumour microenvironment are required both to establish and to maintain tumour growth and survival. The tumour microenvironment may also protect from complete treatment eradication of the malignant cells and result in minimal residual disease that could eventually lead to relapse [2].
Thanks to the introduction of next-generation sequencing technologies, the genetic landscape of B-cell malignancies has been rapidly uncovered, identifying recurrent genetic events that affect key pathways and processes involved in disease pathogenesis, such as B-cell receptor, NF-κB, NOTCH, and JAK-STAT signalling as well as DNA damage response, apoptosis and cell cycle regulation. Notably (and perhaps unexpectedly), as pointed out in the third review by Rosenquist et al., other cellular processes such as immune regulation, epigenetic regulation and RNA processing have also been identified to be involved [3]. Whilst some of these pathways and processes are commonly altered in several B-cell malignancy subtypes, others are mainly observed in one or a few selected subtypes. Some of these genetic lesions have already been shown to have diagnostic and prognostic impact and in some instances even predictive impact. At the same time, novel types of targeted therapy have been developed that affect some of these pathways with promising results.
New targeted treatment strategies in B-cell malignancies primarily include inhibition of tyrosine kinases in the B-cell receptor pathway alone or in combination with traditional chemotherapeutic agents [4]. As the B-cell receptor pathway is unique for B lymphocytes, it can be targeted with high specificity by pharmaceutical agents. Since the first B-cell receptor inhibitor was released for clinical use almost 10 years ago, there has been a huge development of small molecules targeting different pathway kinases. As outlined in the fourth review by Jerkeman et al., four classes of B-cell receptor inhibitors are currently used in clinical trials, inhibiting Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), spleen tyrosine kinase (SYK) or protein kinase Cβ (PKCβ) [4]. Whereas B-cell receptor inhibition has been particularly successful in chronic lymphocytic leukaemia, mantle cell lymphoma and Waldenstrom macroglobulinemia, their future role is more unclear in aggressive subtypes such as diffuse large B-cell lymphoma and transformed lymphomas.
In summary, there has been a dramatic increase in our understanding of the types of genetic events and microenvironmental triggers that contribute to the development of B-cell malignancies. This development has already led to the introduction of new targeted therapies in standard clinical care with considerable improvements in outcome for selected patient groups. Continued efforts promise to pave the way for true precision medicine in this complex group of tumours in the future.
