Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin’s lymphoma that generally affects older individuals and continues to have one of the worst outcomes of all the lymphomas. Over ...the last decade, there has been a widespread adoption of cytarabine-based therapy in younger patients, and the incorporation of rituximab into chemotherapeutic regimens has become an evidence-based standard of care. However MCL remains a largely incurable disease, and following relapse, it can be a challenge to manage. Although it is possible to define prognosis reliably, there are, as yet, no clear diagnostic or response-adjusted parameters that can help to guide therapeutic decisions. However, there are a number of highly active targeted therapies that are moving into the clinic that are set to transform the therapeutic paradigm for this disease in the very near future. This review will explore the molecular pathogenesis of MCL and the current and evolving therapeutic strategies for this disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this issue of
Blood
,
Sarkozy et al
1
demonstrate that the genomic profile of B-cell lymphomas with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin ...lymphoma (CHL), often referred as gray zone lymphomas (GZLs), differs according to their topographic location in anterior mediastinum (thymic niche) or extramediastinal regions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MYC is a potent oncogene initially identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. MYC gene alterations have been identified in other mature B-cell ...neoplasms that are usually associated with an aggressive clinical behavior. Most of these tumors originate in cells that do not normally express MYC protein. The oncogenic events leading to MYC up-regulation seem to overcome the inhibitory effect of physiological repressors such as BCL6 or BLIMP1. Aggressive lymphomas frequently carry additional oncogenic alterations that cooperate with MYC dysregulation, likely counteracting its proapoptotic function. The development of FISH probes and new reliable antibodies have facilitated the study of MYC gene alterations and protein expression in large series of patients, providing new clinical and biological perspectives regarding MYC dysregulation in aggressive lymphomas. MYC gene alterations in large B-cell lymphomas are frequently associated with BCL2 or BCL6 translocations conferring a very aggressive behavior. Conversely, MYC protein up-regulation may occur in tumors without apparent gene alterations, and its association with BCL2 overexpression also confers a poor prognosis. In this review, we integrate all of this new information and discuss perspectives, challenges, and open questions for the diagnosis and management of patients with MYC-driven aggressive B-cell lymphomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Two studies in this issue identify the landscape of somatic mutations in Burkitt lymphoma and highlight the pathogenic and clinical relevance of inactivating mutations of ID3, an inhibitor of the ...TCF3 transcription factor.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are 2 well-defined entities that diverge in their basic pathogenic mechanisms and clinical evolution but they share epidemiological ...characteristics, cells of origin, molecular alterations, and clinical features that differ from other lymphoid neoplasms. CLL and MCL are classically considered indolent and aggressive neoplasms, respectively. However, the clinical evolution of both tumors is very heterogeneous, with subsets of patients having stable disease for a long time whereas others require immediate intervention. Both CLL and MCL include 2 major molecular subtypes that seem to derive from antigen-experienced CD5+ B cells that retain a naive or memory-like epigenetic signature and carry a variable load of immunoglobulin heavy-chain variable region somatic mutations from truly unmutated to highly mutated, respectively. These 2 subtypes of tumors differ in their molecular pathways, genomic alterations, and clinical behavior, being more aggressive in naive-like than memory-like–derived tumors in both CLL and MCL. The pathogenesis of the 2 entities integrates the relevant influence of B-cell receptor signaling, tumor cell microenvironment interactions, genomic alterations, and epigenome modifications that configure the evolution of the tumors and offer new possibilities for therapeutic intervention. This review will focus on the similarities and differences of these 2 tumors based on recent studies that are enhancing the understanding of their pathogenesis and creating solid bases for new management strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating ...multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies. In this review we provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients.
A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among ...hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic lymphocytic leukemia is associated with a highly heterogeneous disease course in terms of clinical outcomes and responses to chemoimmunotherapy. This heterogeneity is partly due to genetic ...aberrations identified in chronic lymphocytic leukemia cells such as mutations of TP53 and/or deletions in chromosome 17p del(17p), resulting in loss of one TP53 allele. These aberrations are associated with markedly decreased survival and predict impaired response to chemoimmunotherapy thus being among the strongest predictive markers guiding treatment decisions in chronic lymphocytic leukemia. Clinical trials demonstrate the importance of accurately testing for TP53 aberrations both del(17p) and TP53 mutations before each line of treatment to allow for appropriate treatment decisions that can optimize patient outcomes. The current report reviews the diagnostic methods to better detect TP53 disruption, the role of TP53 aberrations in treatment decisions and current therapies available for patients with chronic lymphocytic leukemia carrying these abnormalities. The standardization in sequencing technologies for accurate identification of TP53 mutations and the importance of continued evaluation of TP53 aberrations throughout initial and subsequent lines of therapy remain unmet clinical needs as new therapeutic alternatives become available.
The World Health Organization classification of lymphoid neoplasms updated in 2008 represents a worldwide consensus on the diagnosis of these tumors and is based on the recognition of distinct ...diseases, using a multidisciplinary approach. The updated classification refined the definitions of well-recognized diseases, identified new entities and variants, and incorporated emerging concepts in the understanding of lymphoid neoplasms. However, some questions were unresolved, such as the extent to which specific genetic or molecular alterations define certain tumors, and the status of provisional entities, categories for which the World Health Organization working groups felt there was insufficient evidence to recognize as distinct diseases at this time. In addition, since its publication, new findings and ideas have been generated. This review summarizes the scientific rationale for the classification, emphasizing changes that have had an effect on practice guidelines. The authors address the criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly. The issue of borderline categories having overlapping features with large B-cell lymphomas, as well as several provisional entities, is reviewed. These new observations chart a course for future research in the field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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