**2.3. "Acute leukemia: the challenge of capturing disease variety"**

The molecular characterization of malignant cells is currently regarded as being as important as the traditional morphological and immunological approaches to diagnosis. This trend is being additionally accelerated by the introduction of novel drugs designed to specifically target the molecular abnormalities responsible for the development of the tumor. Such developments are of fundamental clinical importance, as they increasingly define not just the diseases

**2.2. Information concerning the tumor genome into the routine clinical management is useful for better treatment strategy selection, delivering "the right treatment to** 

The best efficacy would be achieved if treatment is directed toward specific genetic lesions within malignant cells, which have a key role in the pathogenesis of the respective disease, while minimizing damage to normal, healthy cells [11]. Unfortunately, several limitations still restrict the widespread application of this personalized approach, such as (1) various technological and methodological diagnostic problems; (2) insufficient level of our knowledge about the molecular mechanisms involved in the pathogenesis of different malignancies and the prognostic significance of individual molecular abnormalities; and (3) relatively low number of available targeted therapeutic agents approved for clinical use. Therefore, in practical terms, the personalized approach in hemato-oncology comprises а personalized risk stratification: refinement of clinical prognostic models for a better risk stratification and identification of biologic subtypes within pathologically similar diseases; identification of patients suitable for targeted treatment and "response-adapted" changes in therapy in

In several hematological malignancies, such as acute leukemias, MDS, chronic lymphocytic leukemia (CLL), and so on, cytogenetics remains the most important disease-related prognostic factor for predicting remission rate, relapse, and overall survival (OS) [13–15]. In addition, recent genetic studies identified a large number of mutations in most of the hematological malignancies that point to novel pathways involved in the pathogenesis of the respective disease, and some of these molecular abnormalities have allowed substantial improvements in clinical decision making. As a result, the current prognostic models based on genetic abnormalities are nowadays subject to change as new cytogenetic and mutational findings are

Multiple myeloma (MM) is an incurable malignancy characterized by the clonal proliferation of neoplastic plasma cells in the bone marrow that produce monoclonal protein that can be detected in the serum or urine. MM is a highly heterogeneous disease composed of multiple molecularly defined subtypes, each with varying clinico-pathological features and disease outcomes. Cytogenetically, there are two main subtypes: (1) hyperdiploid myeloma—characterized by trisomies of certain odd-numbered chromosomes and generally associated with a better survival; and (2) nonhyperdiploid myeloma—characterized by translocations of the immunoglobulin heavy chain alleles at chromosome 14q32 with various partner chromosomes, the most important of which are 4, 6, 11, 16, and 20. Several abnormalities have been reported to be associated with poor prognosis, such as t(4;14)(p16;q32)/IGH-MMSET, t(14;16)(p32;q23)/

revealed, contributing to refine better and better these approaches.

themselves but how an individual patient should be treated.

**the right patient at the right time"**

6 Hematology - Latest Research and Clinical Advances

individual patients [12].

The many levels of morphological, immunophenotypic, clinical, genetic, and epigenetic heterogeneity of acute leukemias represent an extraordinary challenge to our capability to understand and to beat these diseases (Löwenberg modified [17]). Acute leukemias were incurable 50 years ago. Significant progress has been achieved by applying intensive regimes and transplantation programs. The 5-year survival rate of people of all ages with acute lymphoblastic leukemia (ALL) increased from 41% for those diagnosed from 1975 to 1977 to 71% for those diagnosed from 2006 to 2012; however, with considerable variations depending on several factors, including biologic features of the disease and a person's age, the 5-year survival rate for people with acute myeloid leukemia (AML) is still approximately 27% which is fairly unsatisfactory [www.cancer.net]. Many recent biologic insights have shed light on these challenging nosological categories, and attempts have been devoted to develop strategies for improved outcomes.

According to the European LeukemiaNet (ELN) recommendations for the diagnosis and management of acute myeloid leukemia in adults (2017), several genetic abnormalities are associated with the response to therapy and survival, allowing to stratify patients into three genetic risk groups [18]:

**Favorable:** t(8;21)(q22;q22.1)/*RUNX1-RUNX1T1;* inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/*CBFB-MYH11;* Mutated *NPM1* without *FLT3*-ITD or with *FLT3*-ITDlow, Biallelic mutated *CEBPA;*

**Intermediate:** Mutated *NPM1* and *FLT3*-ITDhigh, wild-type *NPM1* without *FLT3*-ITD or with *FLT3*-ITDlow (without adverse-risk genetic lesions); t(9,11)(p21.3;q23.3)/*MLLT3-KMT2A*, cytogenetic abnormalities not classified as favorable or adverse;

**Adverse:** t(6;9)(p23;q34.1)/*DEK*-*NUP214;* t(v;11q23.3)/*KMT2A* rearranged; t(9;22)(q34.1; q11.2) /*BCR*-*ABL1;* inv(3)(q21.3q26.2) or t(3,3)(q21.3;q26.2)/*GATA2*,*MECOM (EVI1);* −5/del(5q); −7; −17/abn(17p); complex karyotype, monosomal karyotype; wild-type *NPM1* and *FLT3*-ITDhigh, mutated *RUNX1,* mutated *ASXL1,* and mutated *TP53*.

AML with t(8;21) or inv(16)/t(16;16) is commonly referred to as core-binding factor (CBF) AML, because in both, the heterodimeric protein complex CBF is affected, which is involved in the transcriptional regulation of normal hematopoiesis. CBF-AMLs in patients treated with cytarabine-anthracycline-based induction and high-dose consolidation are considered to have relatively good prognosis compared to other leukemia subtypes, with 10-year OS, disease-free survival (DFS), and event-free survival (EFS) of 63.9, 54.8, and 49.9%, respectively [19]. Nevertheless, 40–45% of these patients eventually relapse and die of their disease. Integration of cytogenetic results with molecular genetics and epigenetic data refines the risk stratification of CBF AML. Several variables might worse prognosis of these patients, such as the level of the respective fusion transcripts *RUNX1-RUNX1T1* and *CBFB-MYH11* [20]. Some authors even suggested that *FLT3*-ITDs carriers constitute a biologically distinct group of APL patients [21].

diagnosis, reduce the cost of the diagnostic workup, and optimize the assignment of patients

Introductory Chapter: Hematology in Times of Precision and Innovation

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

9

Rare conditions pose a number of problems in both theoretical and practical terms. Myeloid sarcoma has been recognized for more than a century; however, owing to the rarity of the entity, most of the study comprises small retrospective studies and case reports. Myeloid sarcoma can occur under different clinical scenarios including an extramedullary leukemic tumor with concurrent AML, preceding the blood and bone marrow involvement or without any history of myeloid neoplasia, as well as an extramedullary AML relapse. These phenomena may not share common mechanisms and outcomes and may need to be treated differently [26]. Kahali Bhaskar presents a review of current published data regarding the incidence, clinical presentation, morphological, cytogenetic and immunophenotypic features, progno-

"Benign hematology isn't so benign" if we use the words of Prof. Alice Ma in ASH Clinical News (2015). Clotting disorders, anemias, thrombocytopenias, and so on may present as seri-

Coagulation is a dynamic process, and the understanding of blood coagulation system and the ways to modulate the process have been evolving significantly. The concept of coagulation originates back to the 1960s when Davie, Ratnoff, and Macfarlane described their cascade theories [27]. Hemostasis is a complex physiological process that maintains the blood flow and is regulated by a delicate balance between procoagulants supporting the formation of hemostatic plugs to prevent the leakage or blood loss and anticoagulants, preventing the formation of unwanted clots. The imbalance between the two components may cause either bleeding or thrombosis. The seventh chapter comprises a review of the defects in the coagulation system and the recent clinical modulators of the coagulation

The different hereditary and acquired defects of the finely regulated coagulation systems might result in severe of even life-threatening bleeding complications or thrombotic events. The recent advances in the knowledge about the structure, function, and regulation of the coagulation system, as well as in the hereditary genetic abnormalities leading to qualitative and/or quantitative defects of the multiple elements of clothing cascade, and acquired disorders of coagulation as a consequence of other underlying conditions, were an important prerequisite of the development of new diagnostic tools and therapeutic strategies based on the product of recombinant technology. The understanding of the physiology of these processes is crucial to identify the pathological scenarios and to predict clinical consequences in order to implement the relevant therapeutic interventions. In combination with the classical

to a particular therapy.

system by Pilli Vijaya.

sis, and treatment of this rare neoplastic myeloid entity.

ous as malignant disorders and are a field of significant progress too.

**3.1. New therapies improve the outlook of bleeding and clotting disorders**

**3. Benign hematological disorders**

Almost half of AML is normal cytogenetically, and this subgroup shows a remarkable heterogeneity in terms of genetic mutations and response to therapy. In patients with normal karyotype, as well as in cases with chromosome abnormalities with intermediate prognosis, the intensity of therapy is driven by the prognostic subgroup. Therefore, the current standard of care combines cytogenetic results with testing for mutations in *FLT3, NPM1, CEBPA,* and *KIT* to precise the risk. The presence of *NPM1* and *CEBPA* gene mutations is associated with a favorable prognosis, however, only in the absence of *FLT3-*ITD [22].

Several other gene alterations (mutations in *WT1*, *RUNX1*, *ASXL1*, *TP53*, *IDH1, IDH2, DNMT3A* genes, partial tandem duplication of *MLL* gene, overexpression of *BAALC*, *MN1, EVI1, ERG*, *WT1*) have also been demonstrated to predict prognosis and probably will play a role in future risk stratification, although some of these have not been confirmed in multiple studies or established as the standard of care [23].

About 30% of AML have an unfavorable karyotype, and if treated with conventional chemotherapy, a complete response rate of about 50% and a 5-year OS of 10–20% are expected. The best chance for patients with an unfavorable karyotype who achieve a complete response is the allogeneic HSCT [24].

A major achievement is the incorporation of genetic and molecular data in the current classification systems. However, the major principle of the World Health Organization (WHO) Classification of tumors of hematopoietic and lymphoid tissues (2016) is to integrate these data with essential clinical features, morphology, and immunophenotyping in order to define distinct disease entities of clinical significance [25]. Morphology is the gold standard, and though it has been the classical tool for diagnosis and classification, it is routinely performed by subjective microscopic evaluation and is strongly dependent on the morphologist's expertise. To extract more accurate and detailed information from patient tissue samples, digital pathology integrated with advances in machine learning is emerging as a powerful tool to enhance morphology-based decisions. In the fifth chapter in this book, Cecilia Lantos et al. provide up to date information about the possibilities that computational histology can provide to improve leukemia diagnosis with an automated biologically meaningful pattern recognition, as well as the additional contribution of deep-learning approach for a higher accuracy. The authors claim that if mathematical pattern recognition methods that recognize cellular phenotypes from microscopic slides and define how morphological features relate to clinical genetic data and protein signatures, this could significantly speed up leukemia diagnosis, reduce the cost of the diagnostic workup, and optimize the assignment of patients to a particular therapy.

Rare conditions pose a number of problems in both theoretical and practical terms. Myeloid sarcoma has been recognized for more than a century; however, owing to the rarity of the entity, most of the study comprises small retrospective studies and case reports. Myeloid sarcoma can occur under different clinical scenarios including an extramedullary leukemic tumor with concurrent AML, preceding the blood and bone marrow involvement or without any history of myeloid neoplasia, as well as an extramedullary AML relapse. These phenomena may not share common mechanisms and outcomes and may need to be treated differently [26]. Kahali Bhaskar presents a review of current published data regarding the incidence, clinical presentation, morphological, cytogenetic and immunophenotypic features, prognosis, and treatment of this rare neoplastic myeloid entity.
