Acute Leukemias - Republican Scientific Medical Library

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a 20.3 · MRD Monitoring in Clinical Trials of ALL 251 rangements can be relatively costly and time-consuming. In the latter case, to reduce the costs associated with designing fluorescent probes that match patient-specific sequences, “consensus” probes matching recurring germ line segments, such as V [47], J [48], and Kde regions [49] that are applicable to multiple patients can be used. Another concern is clonal evolution, secondary rearrangements that can occur during the disease course which may result in the loss of the specific junctional region identified at diagnosis, thereby producing false-negative MRD results. Therefore, it has been recommended that two or more independent PCR targets for each patient are used to monitor MRD [22, 23, 50]. 20.3 MRD Monitoring in Clinical Trials of ALL 20.3.1 MRD Studies in Pediatric ALL Measurements of MRD during therapy of pediatric ALL have demonstrated the ability to provide crucial information about the response to treatment and the risk of relapse. A number of large-scale prospective trials have been performed that illustrate the prognostic value of MRD measurements during the first weeks of therapy. The group at St. Jude Children’s Hospital evaluated MRD on day 19 of remission induction therapy in a large cohort of 110 children treated at their center using flow cytometric techniques [51]. They found unique phenotypic markers for MRD monitoring in 90% of the children using their panel of antibodies. Interestingly, 51 of 110 patients studied achieved a profound remission by day 19 of induction therapy, defined as a MRD level of < 0.01%. The treatment outcome for this group of patients was outstanding, with a 3-year cumulative incidence of relapse of 1.9 ± 1.9% for this group as compared to 28.4 ± 6.4% for patients with MRD levels ³0.01% (p < 0.001). The independent prognostic value of MRD quantification has also been observed when FC MRD monitoring is performed during the first weeks of remission induction therapy (Table 20.2) [52–58]. These studies emphasize the point that this technology is feasible and useful as a prognostic marker and can provide quantitative MRD information, even when samples are sent from participating clinical centers to a central referral laboratory for analysis. However, since a standardized quantitative FC protocol has not yet been developed and accepted, a careful compar- ison of results from different centers is difficult to accomplish. In contrast, during the last several years, the European pediatric centers have begun to adopt a standardized protocol for PCR-based MRD quantification of IgH and TCR gene rearrangements [24, 46]. In a landmark paper, Cave and colleagues [59] demonstrated that measurement of MRD level in early remission was the most important predictor of clinical outcome in 178 children treated in a large French cooperative group study. These investigators, using a semiquantitative technique, showed that detection of high MRD levels (defined as >10 –2 ) after achievement of morphologic remission were strongly predictive of relapse; whereas, patients with very low levels of MRD had similarly good outcomes as those patients in whom no MRD was detected. Indeed, other investigators have also suggested that it may not be essential to eradicate all MRD in order to achieve prolonged DFS [60]. The precise nature of these residual clonal cells that do not appear to give rise to relapse remains to be defined, but may highlight the multistep pathogenesis that is presumed to be responsible for the development of acute leukemia. These studies also suggest that MRD measurement at a single treatment time-point may not provide sufficient clinical prognostic information and that serial MRD measurements augment the predictive capacity of the test. In another large study of MRD involving 240 children with ALL, van Dongen et al. [61] found that combining semiquantitative MRD information from several time-points during treatment identified three risk groups. Fortythree percent of patients were in a low-risk group with a 3-year relapse rate of only 2%; 43% were in an intermediate-risk group with a relapse rate of 23%; and 15% were in a high-risk group with a 75% relapse rate. Other studies confirm the significance of serial, quantitative measurements of MRD [41, 62–67]. These and other PCR-based MRD studies are summarized in Table 20.3. Investigators have also compared MRD results in blood and marrow to determine whether monitoring using blood samples, which is far more accessible and tolerable for patients, yields similar results to bone marrow MRD monitoring [51, 68–75]. To date, the data suggest that blood monitoring may yield comparable results to marrow MRD levels for patients with T-lineage ALL using both flow cytometric and PCR-based methods [51, 71]. The results of blood MRD detection with precursor-B ALL, however, do not seem to be as
252 Chapter 20 · Minimal Residual Disease Studies in <strong>Acute</strong> Lymphoblastic Leukemia Table 20.2. Selected flow cytometry MRD studies Study N Timing Relapse/MRD Major conclusion Ciudad 1998 [56] Ciudad 1999 [109] Dworzak 2000 [58] Coustan 2000 [55] Coustan 2002 [110] Dworzak 2002 [53] Krampera 2003 [77] *C, children; *A, adults 53C/A* After induction therapy 45C* After induction During maintenance After Rx 63C* Median 4 months after CR 195C* End of induction Week 14 Week 32 MRD (+) MRD (–) 27/30 5/23 (90%) (21%) 9/19 (47%) 13/13 (100%) 21/21 (100%) 10/14 (71%) 19/42 (45%) 10/18 (55%) 4/4 (100%) 10/41 (24%) 19/55 (34%) 9/38 (23%) 10/49 (20%) 2/123 (1%) 1/14 (7%) 2/8 (25%) Gradual increase in MRD levels showed a higher relapse rate and shorter median RFS Significant increase in immature B-cell subsets or an altered B-cell differentiation predicts a high relapse rate (P
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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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Page 269 and 270: Subject Index A aberrant methylatio
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