Page: 3-41 (39)
Author: Paolo Giannoni and Daniela de Totero
Chronic lymphocytic leukemia (CLL) is a B cell malignancy characterized by the accumulation of mature monoclonal CD5-positive B cells in the blood, secondary lymphoid tissues and marrow. Despite much advancement in therapy during the last decade, CLL is still considered an incurable disease. The combination of different drugs such as fludarabine, cyclophosphamide and rituximab (FCR) have led to improved progression free-survival and overall survival but only 45% of patients achieve a complete remission and nearly all patients eventually relapse.
Chronic lymphocytic leukemic cells are characterized by an apparent longevity in vivo which is lost when they are cultured in vitro. This observation suggests that cellular interactions and factors provided by the microenvironment are essential to cell survival and may protect leukemic cells from the cytotoxicity of conventional therapies. Moreover the infiltration of CLL cells in lymphoid tissue and in bone marrow is a key element in disease pathogenesis and correlates with clinical stage. Increasing emphasis is now placed on understanding the leukemic/stromal cells cross-talk to identify signals supporting disease progression and to explore novel therapies targeting the microenvironment. This review will focus on critical cellular and molecular pathways of CLL-microenvironment interactions: in vitro and in vivo models for studying the CLL microenvironment will be discussed and new strategies that are being evaluated to disrupt protective signals that support expansion of the neoplastic B cell clone will be described.
Page: 42-61 (20)
Author: Jacob Peedicayil
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Epigenetics, the study of heritable changes in gene expression not involving changes in DNA sequence, plays a key role in the pathogenesis of cancers like myelodysplastic syndrome (MDS) and leukemias. This chapter discusses the role of epigenetics in the pathogenesis of MDS and leukemias. The study of epigenetics has impacted pharmacology leading to the development of a new class of drugs, epigenetic drugs, which attempt to reverse epigenetic changes in clinical disorders. At present, most work is being done on two categories of epigenetic drugs : DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi). The chapter discusses the use of epigenetic drugs in the treatment of MDS and leukemias.
Page: 62-102 (41)
Author: Martin H. Bonamino, Barbara Monte-Mor, Cristiana Solza and Ilana Zalcberg
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Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal malignant diseases, including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (MF) and chronic myeloid leukemia (CML). The oncogenic event underlying CML is the 9-22 translocation, resulting in the fusion protein Bcr-Abl. PV, ET and MF are MPNs Bcr-Abl negative characterized by proliferation of one or more myeloid lineages with relatively normal and effective maturation. Excessive production of mature cells involves mainly the erythroid lineage in PV, megakaryocytic lineage in ET and granulocytic and megakaryocytic lineages in MF. Common findings in MPNs patients are hepatosplenomegaly, variable predisposition to thrombotic events, bleeding and transformation to acute leukemia or bone marrow fibrosis.
Standard treatment is the use of Hydroxyurea (HU), but acetylsalicylic acid can also be indicated, especially in ET patients. Bleeding can be the therapeutic treatment of choice for patients with PV.
Recently, great progress has been achieved in understanding the molecular mechanisms of MPNs. A somatic mutation in the JAK2 gene (JAK2 V617F) was described in more than 95% of PV patients and 50-60% of ET or MF patients. JAK2V617F mutation is associated to the myeloproliferative phenotype and quickly turned into a useful clonal marker in the diagnosis and represents therapeutic target of great importance.
Additional mechanisms, such as genetic alterations in genes such as ASXL1, CBL, IDH1, IDH2, RUNX1, TET2, EZH2, LNK, among others, can play a role in MPNs etiophatogenesis. Interestingly, some of these genes were shown to be directly or indirectly implicated in regulation of DNA methylation. Although this mechanism has not been fully elucidated in MPNs, it may have therapeutic potential, as hypomethylating agents are already used in the treatment of myeloid neoplasms.
The development of new drugs is essential for the specific therapy of these diseases and preclinical tests depend on disease models. Cell lines carrying the V617F mutation are important tools for in vitro studies. Patient’s cells can also be used to study in vitro responses to different drugs. For in vivo studies, transgenic mice conditionally expressing the mutation are presented as an interesting model. Alternatively, the generation of iPS cells from patients can help understanding the pathophysiology of these diseases and testing new drugs.
Several new inhibitors for tyrosine kinases of the JAK family have been developed, such as Ruxolitinib, TG101348, Lestaurtinib and XL019. Pre-clinical tests showed different selectivity for each of the JAK family proteins and inhibition of cell proliferation. Clinical trials in phase I and phase II have been performed with some of these inhibitors and at least two of them (Ruxolitinib and TG101348) induced significant clinical response. Ruxolitinib is the first JAK2 inhibitor approved by the FDA for MF treatment. Currently other inhibitors are being developed and aim to achieve molecular remission of the disease, with a real benefit in progression and survival of these patients.
Page: 103-178 (76)
Author: Jiri Minarik and Vlastimil Scudla
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Multiple myeloma (MM) is a hematological malignancy with a very heterogenous presentation, course and prognosis. Despite an immense progress in the understanding of the tumour biology, neoplastic transformation and progression, we still do not know all the processes that contribute to the multistep pathogenesis of this disease.
For quite a long time there have been a lot of efforts at the improvement of therapeutic approaches in order to intensify the treatment to reach a better response rate, and to prolong the overall survival in MM patients. For more than 30 years, combined chemotherapeutic regimens, and later on high-dosed regimens with autologous stem cell transplantation tried to establish the best approach, however, none of the conventional regimens finally turned out to be significantly superior than the regimen MP (melphallan and prednisone) in the elderly, and HD-ASCT (high-dosed chemotherapy with support of autologous stem cell transplantation) in younger patients.
The last 10 years, however, dramatically changed therapeutic outcomes, and the long lasting “golden-standard” treatment schedules were modified substantially. This change was caused by the introduction of the first generation of novel drugs with “biological mechanism of action”. These new drugs are thalidomide, bortezomib and lenalidomide.
Thalidomide, this teratogenic agent whose short sad history started in 1950´s and ended in 1961 was re-discovered for multiple myeloma in 1999. Since then, several randomized studies have confirmed its superiority in the treatment of relapsed and refractory MM as well as in the frontline treatment of the disease. Unlike many other “biological drugs”, the “biological effect” of multiple myeloma is not aimed solely at one pathogenetic pathway, and does not influence the tumor cells only. It relies on the anti-angiogenic and immunomodulatory effects, together with the inhibition of IL-6 (the most prominent MM growth factor), activation of apoptotic pathways and activation of T-cells.
Bortezomib is the first proteasome inhibitor tested on humans. Its unique mechanism of action by the inhibition of proteasome has a specific affinity to the tumor tissue and widely influences all – proliferation, differentiation and apoptosis of myeloma plasmocytes. Laboratory experiments as well as randomized clinical trials brought surprisingly high percentage of response rates with manageable toxicity. Moreover, rapid effect of bortezomib influenced a substantial number of patients with initial renal failure. Very soon, combined regimens with bortezomib became a new “golden standard” in the management of multiple myeloma.
Lenalidomide was first introduced in 2004. This analogue of thalidomide belongs to the group of drugs called IMiDs - immunomodulatory drugs. Similarly as thalidomide, it has a direct antimyeloma effect as well as the effect on immunity system and bone marrow microenvironment. Lenalidomide has many times greater effect on the inhibition of tumor necrosis factor-alpha, and it has less severe toxicity profile than thalidomide. Unlike both, thalidomide and bortezomib, lenalidomide does not cause neuropathy and is well tolerated in most patients, making it one of the most suitable drugs for frontline treatment as well as for the long-term administration.
The aim of the presented chapter is to make an overview of the history, background and therapeutic applications of thalidomide, bortezomib and lenalidomide in multiple myeloma. Advantages as well as drawbacks of individual treatment approaches will be discussed, and supported by the data of recent clinical studies and papers.
Page: 179-224 (46)
Author: Pengfei Xu, Min Liu, Xiaobo Wang, Zhiguo Liu, Weimin Miao and Wenbin Zeng
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Molecular imaging, defined as the in vivo characterization and measurement of biologic processes at the cellular and subcellualr level, has grown exponentially during the past two decades. Many imaging techniques, involving nuclear tomographic imaging, magnetic resonance imaging, X-ray computed tomography, scintigraphy and optical imaging, have been applied in many aspects of preclinical and clinical studies. Compare to conventional readouts, molecular imaging, employing specific molecular probes as the source of image agents, can be performed in the intact organism with sufficient spatial and temporal resolution for studying biological processes in vivo. Therefore, it can provide the potential for the understanding of integrative biology, earlier detection and characterization of diseases, evaluation of treatment, and guiding of drug research. For these reason, most large pharmaceutical companies chose molecular imaging as drug development tool to select candidates and enhance our understanding of disease and drug activity. Hematology refers to the study of etiology, diagnosis, treatment, prognosis, and prevention of blood diseases that affect the production of blood and its components, such as blood cells, hemoglobin, blood proteins, and the mechanism of coagulation. It associates disorders which primarily affect the blood, including anemia, aplastic anemia, leukemia, lymphoma, multiple myeloma and so on. In the past decade the development of imaging agents and the evolution of imaging modalities has led to huge changes in the diagnoses and therapy of haematologic disorders. This chapter summarizes the recent advances on the application of molecular imaging in staging and evaluation treatment response in haematologic diseases, including thrombus, atherosclerosis, lymphoma, myeloma and thrombus, highlighting successes how molecular imaging can be used in the different stages of drug development in hematology research. Prospects of molecular imaging in this area are also presented.
Page: 225-276 (52)
Author: Manju Mamtani and Hemant Kulkarni
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β-thalassemia is the most intensely studied genetic disorder that continues to pose a significant public health challenge in spite of the innumerable and potentially effective treatment options. Specifically, homozygous deletion or subfunctional mutation of the gene contributing the β chains of the adult hemoglobin results in a clinical form referred to as β-thalassemia major. This form of β-thalassemia is hard to treat. The treatment of β- thalassemia major is currently based on the following main principles: a) regular blood transfusion with treatment aimed at reducing tissue deposition of iron; b) modulation of the fetal hemoglobin (HbF) switch to restart the production of HbF; c) allogeneic hematopoietic stem cell transplantation; and d) approaches aimed at preventing or treating the common complications of β-thalassemia major like infections, cardiac and hepatic dysfunction and osteoporosis. The past decade has witnessed path-breaking advances with regard to all of these therapeutic alternatives. For example, iron chelators like desferrioxamine, deferasirox and deferiprone have led to an increased patient compliance and decreased rates of iron deposition; more accurate diagnostic methods based on the magnetic resonance imaging have helped to better define and plan management of iron overload; several classes of HbF inducers have been identified and exciting opportunities are being recognized based on a combination of these inducers; a plethora of agents are available for the prevention and treatment of common complications; and, most significantly, phenomenal advances have been made in the direction of gene therapy of β- thalassemia major. In this chapter, we present a compiled account of the recent advances on these fronts and also conjecture on the possible future directions these achievements are likely to take.
Integrating Computational Methods, Molecular Docking, and Molecular Dynamics Simulation Approaches Towards Personalized Medicine in Hematological Disorders
Page: 277-325 (49)
Author: George Priya Doss C and Chiranjib Chakraborty
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Recent advances and cost reduction in high-throughput genotyping, microarray technology, and next generation sequencing have generated a tremendous amount of human genetic variation data, determining the effects of amino acid substitution will be the next challenge in mutation research. There has been much effort in current epidemiology, medicine, phamarcogenomics studies and personalized medicine in identifying the genetic variations. Among the types of variation, such as Single-nucleotide polymorphisms (SNPs), indels, microsatellites, copy number variants, and epigenetic markers, SNPs were found to be useful and widely applied markers in genetic studies. This flood of data has lead to the creation of bioinformatic databases and software’s which are helpful in discriminating the disease associated variants from neutral ones. Understanding the genotype–phenotype relationship through SNPs is the first and most important step in drug research and development. Building bridges between clinical findings and bioinformatics’ resources will open new possibilities in diagnostic and therapeutic efforts. Several studies have described the application of computational resources, but this section will address the SNP bioinformatics tools, critical databases and their uses, in personalized medicine will tailor treatments to the patients’ specific genotype. The principle aim is to provide a computational pipeline for hematologists conducting cost effective and time consuming SNP-centered research by the application of computational methods, molecular docking, and molecular dynamics simulation approaches in ABL1 gene. This section addresses the powerful and practical applications of bioinformatics in hematological disorders.
Page: 326-362 (37)
Author: Maria Lukasik and Slawomir Michalak
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Aspirin (acetylsalicylic acid, ASA) is widely used in the secondary prevention of cerebrovascular diseases (CVD). The double function of the drug is considered in vascular diseases. The antithrombotic effect of ASA is dependent on inhibition of TxA2-induced platelet activation whereas the anti-inflammatory effect of ASA may be secondary to decreased platelet activation or it may be directly related to the NF-B-dependent induction of adhesion molecules in endothelial cells followed by monocyte adhesion. There are only a few conflicting data concerning the impact of ASA on platelet pro-inflammatory activation markers. The effectiveness of aspirin in vascular diseases was confirmed in the cited milestone large clinical trials and ASA is recommended by international scientific societies as the antiplatelet drug of first choice in prevention of vascular disease. The role of acetylsalicylic acid is extensively studied for its nonvascular effects as well. The background for experimental and clinical studies, as well as for meta-analyses, is the involvement of inflammatory pathomechanisms of neurodegeneration. Microglial activation and modification of the inflammatory processes in the central nervous system by acetylsalicylic acid and its neuroprotective potential will be discussed in the light of expected clinical benefits. Aspirin’s effect on the course of Parkinson’s or Alzheimer’s disease remains ambiguous in the clinical studies; therefore meta-analyses focus on identification of the drug’s advantages. Up-regulated degradation of the drug by the spectrum of esterases will be presented in relation to the practical aspects of aspirin administration. Moreover, aspirin may inhibit carcinogenesis apparently through inhibition of COX-2, induction of apoptosis and its favourable effect on the DNA mismatch repair system. The limited effectiveness of ASA may result from the phenomenon of biochemical or clinical aspirin resistance. Both pharmacokinetic and pharmacodynamic factors or disease-related mechanisms may be involved. Laboratory assays used for detection of aspirin resistance require optimization, which will be discussed from the point of view of good laboratory practice and clinical usefulness. Widely used ASA should be considered as a drug modifying the results of routine laboratory tests. The interpretation of results (e.g. creatinine, amylase, valproate) in aspirin-treated patients involves drug interference with the laboratory assays. Finally, the risk of aspirin-related complications of invasive procedures and diagnostic tests (e.g. lumbar puncture, electromyography, angiography) is considered in everyday neurological practice.
Frontiers in Clinical Drug Research – Hematology is an eBook series that brings updated reviews to readers interested in learning about advances in the development of pharmaceutical agents for the treatment of hematological disorders. The scope of the eBook series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs employed in the treatment of anemias, coagulopathies, vascular diseases and hematological malignancies. Reviews in this series also include research on specific antibody targets, therapeutic methods, genetic hemoglobinopathies and pre-clinical / clinical findings on novel pharmaceutical agents. Frontiers in Clinical Drug Research – Hematology is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of hematology, oncology and vascular pharmacology. The first volume of this series features 6 chapters that cover a variety of topics including: Computational methods, molecular docking, and molecular dynamics simulation Recent advances in the treatment of Beta-Thalassemia Major Research on multiple myeloma and leukemia Molecular imaging in hematology