Acute Leukemias - Republican Scientific Medical Library

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Novel Therapies in <strong>Acute</strong> Lymphoblastic Leukemia Stefan H. Faderl, Hagop Kantarjian Contents 19.1 Introduction ................... 237 19.2 New Chemotherapy Agents ....... 238 19.2.1 Liposomal Preparations ....... 238 19.2.2 Nucleoside Analogs .......... 239 19.2.3 Epigenetic Therapy .......... 240 19.2.4 Signal Transduction Inhibitors . . 241 19.2.5 Monoclonal Antibody Therapy . . 241 19.2.6 Other Agents .............. 242 19.2.6.1 Pegylated Asparaginase . 242 19.2.6.2 Forodesine (BCX-1777) . . 242 19.3 Getting to Know Chemotherapy: The Role of Pharmacogenetics and Mechanisms of Drug Resistance .... 243 19.4 Conclusion .................... 244 References ......................... 244 19.1 Introduction Although prognosis of adult ALL has improved over the last few decades, still only 30–40% of patients achieve long-term, disease-free survival and can be considered cured [1, 2]. The remainder will eventually relapse and die from disease progression or other ALL-related consequences. New strategies, refinements of old ones, and novel agents are therefore needed. How modifications of induction regimens can positively impact the outcome in subsets of the disease is exemplified in mature B-cell ALL where short, dose-intensive chemotherapy leads to survival of 50–70% of the patients and T-cell ALL in which addition of cyclophosphamide, high-dose methotrexate and cytarabine in the induction and consolidation sequence is associated with similar survival rates [3]. Other subgroups such as Philadelphia chromosome-(Ph) positive ALL are still largely incurable with chemotherapy alone although the combination of BCR-ABL tyrosine kinase inhibitors with intensive chemotherapy is showing promising leads in this group of patients as well. Several paths to better treatment strategies can be pursued and must not be seen isolated from each other: (1) continuous modification of current therapy programs in light of a better understanding of disease subtypes and regimen-specific components; (2) development of new drugs targeted against identifiable cytogenetic-molecular abnormalities; and (3) appreciation of the role of pharmacogenetics in ALL and developing mechanisms to overcome drug resistance. Successful implementation of any of those strategies ultimately requires a more profound understanding of the biological characteristics of ALL taking into account the heterogeneity of ALL. Given the complexity of ALL treatment programs, it can hardly be expected that there is a single new agent that will stand out on its own so that progress in ALL will require not only integration of new agents into treatment algorithms, but also to learn how to better use the armamentarium of currently available agents and combinations (Table 19.1) [4].
238 Chapter 19 · Novel Therapies in <strong>Acute</strong> Lymphoblastic Leukemia Table 19.1. Novel strategies in ALL Class of agents/parameters Examples 1. New agents Liposomal and pegylated formulations Liposomal vincristine Pegylated asparaginase (pegaspargase) Nucleoside analogs Clofarabine Nelarabine Purine nucleoside phosphorylase (PNP) inhibitors Forodesine (BCX-1777) Oligonucleotides BCL-2 antisense Proteasome inhibitors Bortezomib (Velcade) Tyrosine kinase inhibitors Imatinib Nilotinib Dasatinib Semaxinib (SU5416) Farnesyltransferase inhibitors Tipifarnib (R115777) Lornafarnib (SCH66336) Monoclonal antibodies Rituximab (anti-CD20) Alemtuzumab (anti-CD52) Anti-CD19 + ricin/genistein/PAP Anti-CD7 + ricin 2. Modifications of induction regimens Supportive care Laminar air flow room for older patients (>60 years) Risk-adapted CNS prophylaxis Adjust number of intrathecal therapy Examine role of craniospinal XRT Maintenance Duration Intensification Role of asparaginase 3. Pharmacogenetics and mechanisms of drug resistance 19.2 New Chemotherapy Agents 19.2.1 Liposomal Preparations Liposomal preparations of chemotherapeutic agents change the pharmacological properties of the original and active compound resulting in most cases in better efficacy with reduced toxicity. Several liposomal agents are being investigated in ALL salvage therapy among which liposomal (sphingosomal) vincristine and pegylated asparaginase (see below) have received the most attention. Vincristine has been an active anticancer agent for many years and is widely used in the treatment of numerous malignancies, but neurotoxicity is a frequent DLT. The therapeutic activity and drug toxicity of vincristine can be improved by encapsulating vincristine into a liposomal delivery system [5]. Changes in the pharmacological properties are reflected by a comparison of plasma half-lives between the active compound
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E.H. Estey · S.H. Faderl · H. M.
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E. H. Estey Department of Leukemia
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VI Table of Contents 14 Philadelphi
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VIII Contributors S. H. Faderl Depa
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X Contributors D. Wartenberg Depart
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Therapy of AML Elihu Estey Contents
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a 1.2 · Standard Therapy 3 Table 1
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a 1.2 · Standard Therapy 5 Table 1
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a 1.2 · Standard Therapy 7 tween G
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a 1.2 · Standard Therapy 9 Fig. 1.
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a 1.2 · Standard Therapy 11 of tre
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a 1.2 · Standard Therapy 13 Table
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a 1.2 · Standard Therapy 15 permit
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a References 17 19. Care RS, Valk P
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a References 19 6-thioguanine in th
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Acute Myeloid Leukemia: Epidemiolog
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a 3.1 · Epidemiology 49 3.1.4 Gend
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a 3.2 · Etiology 51 part of the in
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a 3.2 · Etiology 53 for the develo
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a References 55 38. Crane MM, Stom
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Relapsed and Refractory Acute Myelo
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a 4.2 · Prognostic Factors in Pati
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a 4.3 · Treatment of Relapsed and
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a 4.4 · Hematopoietic Stem Cell Tr
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a 4.6 · Gemtuzumab Ozogamicin 65 T
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a 4.7 · Relapsed and Refractory Ac
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a 4.7 · Relapsed and Refractory Ac
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a References 71 The ability of immu
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a References 73 39. Vogler WR, McCa
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a References 75 95. Sievers EL, Lar
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Part II - Acute Lymphoblastic Leuke
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78 Chapter 5 · Acute Lymphoblastic
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Molecular Biology and Genetics Meir
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a 6.3 · Structural Aberrations 97
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a 6.3 · Structural Aberrations 99
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a 6.5 · Molecular Aberrations 101
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a References 103 clear that homozyg
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a References 105 53. Chim CS, Tam C
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a References 107 122. Lennard L, Li
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Diagnosis of Acute Lymphoblastic Le
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a 8.3 · Cytochemistry and Immunoph
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a 8.5 · Cytogenetic and Molecular
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a 8.5 · Cytogenetic and Molecular
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a References 127 including the reti
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a References 129 47. Kita K, Shirak
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Acute Lymphoblastic Leukemia: Clini
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a 7.3 · Diagnosis 111 or neoplasti
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a 7.3 · Diagnosis 113 Fig. 7.2. Hi
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a 7.3 · Diagnosis 115 The vast maj
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a References 117 dren: Biologic bas
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General Approach to the Therapy of
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a 9.3 · New Agents 133 dose methot
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a References 135 4. Gökbuget N, Ho
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138 Chapter 10 · Recent Clinical T
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146 Chapter 11 · Conventional Ther
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ALL Therapy: Review of the MD Ander
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a 12.2 · The Hyper-CVAD Regimen in
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a 12.3 · Subset-Specific Approache
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Treatment of Adult ALL According to
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a 13.2 · Therapy for Younger (15-6
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a 13.3 · Therapy of Ph/BCR-ABL-Pos
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a 13.5 · Prognostic Factors 173 13
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a References 175 Only patients with
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Philadelphia Chromosome-Positive Ac
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a 14.2 · Molecular Biology of the
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a 14.3 · Treatment of Ph+ ALL 181
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a 14.4 · Hematopoietic Stem Cell T
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Page 261 and 262: Emergencies in Acute Lymphoblastic
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Subject Index A aberrant methylatio
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a Subject Index 291 CREB, see enhan
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a Subject Index 293 MUD, see matche
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