Acute Leukemias - Republican Scientific Medical Library

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Minimal Residual Disease Studies in <strong>Acute</strong> Lymphoblastic Leukemia Syed Abutalib, Wendy Stock Contents 20.1 Introduction ................... 247 20.2 Methods for Detection of MRD ..... 249 20.2.1 Flow Cytometric Detection of MRD 249 20.2.2 PCR-based MRD Detection ..... 250 20.3 MRD Monitoring in Clinical Trials of ALL ....................... 251 20.3.1 MRD Studies in Pediatric ALL . . . 251 20.3.2 MRD Studies in Adult ALL ..... 20.3.3 MRD Monitoring in Selected Dis- 254 ease Subsets: t(4;11) and t(9;22) . 20.3.4 Prognostic Significance of MRD in Patients Undergoing Stem Cell 255 Transplantation ............. 20.3.5 The Future: Risk-Adapted Therapy 256 Based on MRD ............. 257 20.4 Summary ..................... 257 References ......................... 259 20.1 Introduction Considerable progress has been made in the treatment of both childhood and adult acute lymphoblastic leukemia (ALL) during the past two decades. The majority of both children and adults achieve a complete remission (CR) while the majority of children are now cured with current therapies, most adults will ultimately experience a relapse and die of their leukemia. The ability to distinguish good-risk patients who are likely to be cured with conventional chemotherapy from those who are likely to relapse has important clinical implications. In both adult and pediatric ALL, relapse is thought to result from residual leukemia cells (as many as 10 10 ) that remain following achievement of morphologic remission and are below the limits of detection using conventional microscopic and cytogenetic assessment of the bone marrow [1–3]. A variety of sensitive techniques have been used to monitor the persistence of the leukemic clone during treatment in an attempt to identify patients who are in morphologic and cytogenetic remission, but in whom there is persistence of subclinical, or minimal residual disease (MRD), and who may be at increased risk for relapse. Moreover, MRD studies in ALL have the potential to provide novel insights into the clinical efficacy of both standard and novel treatment strategies aimed at improving the cure rate. Recent prospective studies designed to validate the clinical significance of MRD detection in ALL are beginning to answer several important questions: 1. Does detection of MRD following achievement of clinical remission predict treatment outcome? 2. If early MRD measurements are predictive of relapse, can MRD detection be used to guide therapy (i.e., can therapy be intensified or reduced based on MRD results)? 3. What is the optimal clinical time-point(s) for MRD assessment? 4. Does clinical intervention based on MRD result improve survival? 5. Is it essential to eradicate MRD (as detected by these highly sensitive assays) in order to achieve a cure? 6. Can peripheral blood monitoring be substitute for bone marrow MRD evaluation?
248 Chapter 20 · Minimal Residual Disease Studies in <strong>Acute</strong> Lymphoblastic Leukemia Table 20.1. Characteristics of major techniques currently employed for detection of MRD in ALL Flow cytometric immuno- PCR analysis of chromo- PCR analysis of IgH/TCR genes phenotypingsome aberration* Sensitivity 10 –3 –10 –4 10 –4 –10 –6 10 –4 –10 –5 Applicability Precursor-B-ALL Children 80–90% 40–50% 95% Adults T-ALL 70–80% 35–45% 90% Children >95% 10–25% >95% Adults >95% 5–10% 90% Advantages Adequate sensitivity Relatively easy and cheap Minimal tissue requirements Applicable for most pa- Sensitive and leukemia Applicable for virtually all patients if tients specific IGH, IGK-Kde, TCRG, and TCRD gene rearrangement are used as targets Quick: (2–3 days) and rela- Stable target during disease Sensitive and patient specific tively cheap course Distinguish living from Rapid: 2–3 days Rapid during follow up: 2–3 days dead leukemia cells (if junctional region is identified and RQ-PCR is used) Suitable for monitoring Applicable for virtually all patients if uniform patient groups IGH, IGK-Kde, TCRG, and TCRD gene (Ph+ ALL) rearrangement are used as targets Minimal tissue requirements Sensitive and patient specific Disadvantages Analysis is quite complex Useful in minority of Time-consuming at diagnosis: iden- and depends on the exper- patients tification of the junctional regions tise of the operator Cross contamination of PCR and sensitivity testing Difficult to distinguish be- products leading to false- Relatively expensive tween normal regenerating positive results (even at Need for preferably two PCR targets bone marrow progenitors diagnosis) per patient because of chance of and residual blasts of B-cell Risk of RNA degradation clonal evolution precursor leukemias and inefficiency during Expert operators have to conversion of mRNA to continuously be available cDNA (which may reduce locally since analysis can the sensitivity of RT-PCR be reliably done only on monitoring leading to fresh cells false-negative results)
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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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a References 185 2. Kurzrock R, Sht
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a References 187 56. Mori T, Manabe
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a References 189 acute lymphoblasti
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192 Chapter 15 · Burkitt’s Acute
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194 Chapter 15 · Burkitt’s Acute
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Page 261 and 262: Emergencies in Acute Lymphoblastic
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Page 265 and 266: a 23.9 · Neurological Complication
Page 267 and 268: a References 287 29. Hingorani AD,
Page 269 and 270: Subject Index A aberrant methylatio
Page 271 and 272: a Subject Index 291 CREB, see enhan
Page 273 and 274: a Subject Index 293 MUD, see matche
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