**2. Hematological malignancies**

Hematological malignancies account for around 8–9% of all cancers, being the fourth to fifth most frequently diagnosed cancer in economically developed regions of the world [1]. The

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

estimated deaths from these tumors account for 7% of the cancer-related deaths [2]. The agestandardized incidence rates are 24.5 (per 100,000) for lymphoid malignancies and 7.55 for myeloid malignancies. The most common lymphoid malignancies are plasma cell neoplasms (4.62), small B-cell lymphocytic lymphoma/chronic lymphocytic leukemia (3.79), diffuse large B-cell lymphoma (3.13), and Hodgkin lymphoma (2.41). The commonest myeloid malignancies are acute myeloid leukemia (AML) (2.96), other myeloproliferative neoplasms (MPN) (1.76), and myelodysplastic syndromes (MDS) (1.24) [3].

are often toxic, elicit incomplete responses, and may have severe long-term negative effects. Besides, despite the improved response and survival rates, drug resistance and relapse remain major problems and several hematological malignancies remain incurable with standard treat-

Introductory Chapter: Hematology in Times of Precision and Innovation

http://dx.doi.org/10.5772/intechopen.76849

5

B-cell lymphomas comprise a rapidly developing field of remarkable transfer of knowledge and understanding into precise diagnosis and effective therapeutic approaches. The dissection of B-cell development has been in the focus of tremendous interest in the recent years. The understanding of normal B-cell biology versus B-cell lymphoma pathogenesis leads us inevitably to the B-cell receptor (BCR) signaling. The expression of a functional BCR retains a crucial role for B-cell survival and proliferation. In this regard, BCR activation and signaling pathways can support the growth and evolution of both normal and malignant B-lymphocytes, and as a result, from the functional perspective, it might act as a true oncogene [7]. Julieta Sepulveda et al. review the BCR as a driver of B-cell lymphoma development and evolution in Chapter 2 of this book and discuss the genetic mechanisms that create a functional antigen receptor and their errors leading to oncogenic events, the pathogenic activation of the B-cell receptor signaling cascade, and introduce some novel emerging therapies

The functional role of the BCR in the pathogenesis and lymphoma progression is particularly well characterized in diffuse large B-cell lymphomas (DLBCL). Gene expression profiling has separated DLBCL into two distinct sub-entities: the germinal center B-cell DLBCL (GCB) and the activated B-cell-like (ABC) DLBCL characterized by ongoing BCR signaling and substantially worse clinical outcomes when treated with standard immunochemotherapy. DLBCL is the most common type of non-Hodgkin lymphoma which accounts for approximately onethird cases of lymphoid malignancies in the Western world. There is a considerable variability in terms of clinical course and therapeutic outcomes due to the unique heterogeneity of biology that exists between and within lymphoma subtypes. In addition to GCB and ABC subtypes, double/triple-hit and double-expressor lymphomas with rearrangements and/ or overexpression of MYC, BCL2, and/or BCL6 genes have also been associated with poor prognosis [8]. However, a number of clinical trials have demonstrated the feasibility of novel agents and combinations with encouraging efficacy [9]. The rapid pace in understanding biological mechanisms, recent molecular subclassification, and clinical developments has moved into the focus of personalization of therapy. The third chapter provides an overview of the

This is yet another demonstration of how hematology has advanced in parallel with technological developments that have expanded our understanding of the phenotypic, genetic, and molecular characteristics of the hematological neoplasms. Dissection of genetic abnormalities critical to leukemia, lymphoma, and myeloma initiation provided insights into the pathogenesis of hematological malignancies, but also identified distinct subsets of patient, predicted prognosis individually, and provided rational therapeutic targets for curative approaches [10].

**2.1. The effective implementation of rationally developed therapies requires rapid** 

ments [6].

**integration of new biological data**

targeting the B-cell receptor at different levels.

recent advances in DLBCL presented by Kumar Vivek.

Hematological malignancies arise through a multistep process of a sequential accumulation of a variety of chromosome aberrations and/or molecular abnormalities in a hematopoietic stem cell or a progenitor cell. These abnormalities affect the normal structure or the function of certain genes resulting in modifications in the genetic programs that control cellular proliferation, differentiation, programmed cellular death (apoptosis), relationships with neighboring cells, and the capacity to escape the immune system [4]. This process leads to the formation of a clone of deregulated cells, which escape the physiological control of normal cell growth and behavior [5].

The spectrum of genetic and epigenetic abnormalities that occur in hematological malignancies is extremely heterogeneous and ranges from single DNA nucleotide changes that affect the coding of a single amino acid to chromosomal gains and losses that disrupt the transcription of hundreds of genes. Frequently, the pattern of genetic defects is highly complex with multiple different abnormalities, such as structural and numerical chromosome aberrations, point mutations, gene amplifications, microdeletions, microinsertions, fusion genes, gene rearrangements, aberrant gene expression, and so on. The diversity in the form of a disease produced results from a combination of factors, particularly the type of cell affected, the nature of the genetic change that precipitates the malignancy, and the point in the cell's maturation process at which the malignant change occurs. Besides, most hematological malignancies are an oligoclonal disease even within a single patient, such that the predominant clone at the initial presentation is not necessarily identical to the clone ultimately responsible for clinical relapse and death. The progression to the overt clinical relapse may be associated (1) with the initial malignant clone that develops chemo-resistance after initial sensitivity to treatment, most frequently due to the acquisition of additional mutations; or (2) with a subclone, which initially presents at low frequency, but given a clonal advantage during treatment, replaces the founder clone and becomes the predominant clone. These add additional biological heterogeneity of the individual patients with one and same diseases.

On the other hand, it is important to specify that the presence of low levels of characteristic "initiating" leukemia- and/or lymphoma-associated molecular abnormalities do not lead directly to disease, even if these abnormalities confer advantages in self-renewal, proliferation or both, resulting in clonal expansion of the affected cells as a "pre-malignant" clone. Using highly sensitive (10−6–10−8) nested primer PCR approaches, a low level of various leukemiaand/or lymphoma-associated molecular abnormalities was detected in a significant proportion of healthy individuals.

Currently, most hematological malignancies are treated with highly cytotoxic drugs, radiation, and/or hematopoietic stem cell transplantation (HSCT), and all these therapeutic approaches are often toxic, elicit incomplete responses, and may have severe long-term negative effects. Besides, despite the improved response and survival rates, drug resistance and relapse remain major problems and several hematological malignancies remain incurable with standard treatments [6].
