Acute Leukemias - Republican Scientific Medical Library

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a 20.3 · MRD Monitoring in Clinical Trials of ALL 255 In long-term survivors, the incidence of a MRD-positive result decreased continuously from a high of 36% following induction therapy to a low of 7% at months 10–24 of treatment. In contrast, 64% and 56% of patients who relapsed were MRD-positive following induction and at 10–24 months, respectively. MRD was a significant predictor of relapse risk at all time points; however, the predictive value of a positive result appeared the strongest between 4 and 9 months following achievement of remission. These investigators found MRD to be a significant prognostic marker in a multivariate analysis. Similarly, using flow cytometric MRD detection, high MRD level (defined as > 10 –3 )atanyof several postremission treatment time-points was associated with a high relapse rate of 94% [56]. From these studies, it appears that MRD assessment at several time-points during treatment might enhance predictive value in adult ALL. The German Multicenter ALL study group (GMALL) found that combining the results of several MRD measurements during the first year of treatment enhances the predictive value of any single time-point. In a recent study, they evaluated the predictive value of quantitative MRD detection in 196 standard-risk ALL patients in first CR treated on a single German cooperative group study who were monitored sequentially during the first year of treatment. They found that combining MRD values from three time-points during the first 16 weeks of treatment identified three novel risk groups. Patients with a rapid MRD decline (< 10 –4 at day 11 and day 24 of remission induction) had a 3-year relapse rate of 0%. In contrast, those patients with slow MRD decline (MRD of ³10 –4 through week 16 of therapy) had a relapse rate of 94% at three years. The remaining patients fell into an intermediate risk group where the relapse rate was 47%. Thus, MRD quantification during treatment identified new prognostic subgroups within an otherwise homogeneous standard risk subset of ALL who might benefit from risk-adapted therapeutic approaches [81]. 20.3.3 MRD Monitoring in Selected Disease Subsets: t(4;11) and t(9;22) Several smaller studies focusing on the impact of MRD detection in high-risk ALL have been performed using RT-PCR of the leukemia-specific fusion transcripts, MLL-AF4 and BCR-ABL. The MLL-AF4 fusion gene results from the t(4;11) and is found in approximately 3– 6% of adults and children with ALL and is the most common cytogenetic abnormality in infants with ALL [82, 83]. The t(4;11) has been associated with a very poor prognosis when standard chemotherapy is administered, but improved survival has been reported for patients receiving an allogeneic transplant in first remission. A prospective analysis of MRD monitoring in 25 patients with the MLL-AF4 fusion gene is the largest study of this ALL subset and demonstrated, using a qualitative RT-PCR assay, that patients who remained PCR negative 3–6 months following diagnosis enjoyed prolonged survival [84]. In contrast, this and other smaller studies showed that patients who remained PCR-positive or converted from a negative to a positive test following transplant were destined to relapse [83, 85, 86]. Beginning in the late 1990s, studies to assess MRD status following allogeneic stem cell transplantation (allo-SCT) have provided intriguing information about the risk of relapse in Philadelphia chromosome positive (Ph+) ALL patients using RT-PCR monitoring of the BCR-ABL fusion gene transcript [74, 87–93] (Table 20.4). Using qualitative RT-PCR testing with sensitivities reported in the 1 in 10 5–6 range, all of these studies found that patients who were consistently PCR negative following Allo-SCT were unlikely to relapse. Conversely, patients in whom MRD was detected after allo-SCT were at very high risk of relapse. In the largest published series, Radich et al. found that the relative risk of relapse (RR) was significantly higher for patients with detectable BCR-ABL fusion gene transcript following transplantation than for those without detectable transcript (RR = 5.7, p=0.025) [90]. The prognostic significance of the PCR assay remained after controlling for other clinical variables (e.g., stem cell source, presence of graft-vs.-host disease) that could influence relapse risk. Interestingly, the genetic context of MRD may also be of relevance. In their study, Radich noted that the risk of relapse was greatest for PCR+ patients with a p190 BCR-ABL transcript in comparison to patients who had detectable p210 BCR-ABL transcripts after transplantation. The median time from detection of a positive PCR result to relapse was 94 days. MRD detection prior to transplant for Ph+ ALL is also a good predictor of relapse-free survival after Allo-SCT [90, 94]. Based on these data, there has been a concerted effort to eradicate MRD prior to moving forward with transplant for these high-risk patients.
256 Chapter 20 · Minimal Residual Disease Studies in <strong>Acute</strong> Lymphoblastic Leukemia Table 20.4. MRD and outcome: Pre- and Posttransplant Study N Relapse/MRD Major outcome MRD positive MRD negative Vervoordeldonk 1997 13C 8/8 (100%) 0/5 (0%) MRD in harvested BM predicts relapse after [103] transplantation with autologous purged BM in children in 2nd remission of pre-B-ALL Knechtli 1998 [99] 64C 12/12 (100%) 8/38 (21%) 2-year EFS for these groups was 0%, and 73%, respectively (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
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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