Acute Leukemias - Republican Scientific Medical Library

More documents

Recommendations

Info

a 20.4 · Summary 257 of pre- and posttransplant MRD measurements (Table 20.5) [66, 78, 93, 98–105]. Using semiquantitative PCR methods, two large studies in pediatric ALL were able to identify three risk groups based on pretransplant MRD status [98, 99]. For patients who were MRD negative prior to transplant, DFS was 78% in both series; for those with intermediate-level MRD, DFS was 48% and 36%, respectively; and for those with high levels of MRD (but in clinical remission) prior to Allo-SCT, DFS was only 23% and 0%, respectively. The majority of studies reported and summarized in Table 20.5 also suggest that the presence of MRD prior to transplant is associated with significantly higher relapse rates following transplant. In contrast, only one study in adult ALL patients found that MRD detection prior to transplant had no predictive value; whereas, MRD detection following Allo-SCT in this series was highly predictive of relapse [78]. Of the several studies where serial MRD measurements were taken, the presence of MRD following Allo-SCT was an ominous sign, with the majority of these patients relapsing within months following transplant [78, 93, 103, 106, 107]. Taken together with the results described above for the subset of patients with Ph+ ALL, the data suggest that MRD analysis prior to transplant can contribute significant prognostic information and that the goal of pretransplant therapy should be to achieve MRD negative status. Whether RQ-PCR methods will help to refine the prognostic capabilities and guide therapeutic interventions pre- and posttransplant (e.g., novel molecular targeted therapy, early withdrawal of immunosuppressive therapy, posttransplant immunotherapy) remains an open question. 20.3.5 The Future: Risk-Adapted Therapy Based on MRD The demonstration that MRD measurement provides valuable and validated independent prognostic information has led to the implementation of MRD-based riskadapted therapy based on MRD in several pediatric and adult ALL trials. Two general strategies are being evaluated: intensification of postremission treatment (e.g., allogeneic stem cell transplant in first remission) for patients with high levels of MRD, or decreased duration or intensity of treatment for patients with low or undetectable levels of MRD. The Children’s Oncology Group in North America plans to combine two prognostic mark- ers to assign postremission therapy: results of a remission induction day 14 bone marrow examination and a day 29 MRD evaluation. MRD measurements will be performed using a 4-color flow cytometric assay in two central reference laboratories. Patients defined as “high risk” based on these two tests will be assigned to an intensified postremission course of treatment. The Dana Farber ALL consortium also plans to use MRD detection to further stratify postremission therapy. Using RQ-PCR following induction therapy, patients will be assigned to receive additional postremission therapy with daunorubicin and/or cytarabine. In these North American studies, there will be no de-escalation of therapy based on MRD. In contrast, the ongoing European BFM-AEIOP uses the results of RQ-PCR performed in reference laboratories to assign “MRD-high level” patients to Allo-SCT in first remission, while “MRD-low level” patients will receive a reduced course of postremission therapy. In adult ALL, the GMALL group is performing a prospective study with MRDbased treatment decisions after 1 year of chemotherapy in patients considered standard risk according to conventional risk factors described above [81]. For MRD low-risk patients, defined as MRD levels of < 10 –4 at all postremission time-points, treatment will be stopped after 1 year and maintenance therapy will be omitted; whereas, MRD high risk patients, defined as patients with MRD > 10 –4 at any postremission time-point, will have treatment intensification, focusing on Allo-SCT. 20.4 Summary In conclusion, MRD evaluation provides independent prognostic information in both children and adults with ALL. To date, there is quite convincing evidence in both pediatric and adult ALL studies of MRD that a high level of MRD at the end of induction therapy is associated with a higher relapse rate. Furthermore, the continuous detection of high levels of MRD during consolidation and maintenance therapy, the re-emergence, or increase in MRD levels all appear to herald relapse. In contrast, declining or negative MRD results are associated with a favorable prognosis. From the studies that have been completed over the last decade, there appear to be sufficient data to justify the incorporation of MRD status into decisions about postremission treatment assignment and several studies outlined in the section above are now underway using this strategy. MRD evaluation
258 Chapter 20 · Minimal Residual Disease Studies in <strong>Acute</strong> Lymphoblastic Leukemia Table 20.5. MRD studies in Ph+ALL Study N Rx Relapsed MRD-status Major conclusion MRD+ MRD– Gehly 1991 [92] 4 Allo 1/1 (100%) 0/3 (0%) Interval between MRD detection and relapse in Ph+ALL may be relatively short and quite different from Ph+ CML post transplant 2 Auto 1/1 (100%) 1/1 (100%) Miyamura 1992 9 Allo 5/5 (100%) 1/4 (25%) Median interval between PCR positivity and [91] clinical relapse was only 4 weeks 6 Auto 2/2 (100%) 0/4 (0%) Radich 1995 [93] 8 Auto 1/8 (12%) – PCR+ following Allo-SCT predictive of relapse Mitterbauer 1995 7 – 6/6 (100%) 1/1 (100%) One-step combined with two-step RQ-PCR [88] analysis gives valuable information about the efficacy of treatment and the dynamics of the leukemia Radich 1997 [90] 30 Allo 8/21 (38%) 0/9 (0%) Median time from first PCR-positive test to relapse was 94 days 6 Auto 2/2 (100%) 2/4 (50%) p190 confers higher risk of relapse than p210 Sierra 1997 [89] 18 Allo 5/18 (62%) – PCR+ following match Allo-SCT correlates with relapse Preudhomme 1997 8 CT 6/7 (85%) 0/1 (0%) Relapse is always preceded by switch to PCR [87] positivity of Ph+ by 4 to 6 months 5 Allo 3/3 (100%) 0/2 (0%) Lower sensitivity of RT-PCR in PB compared with BM 4 Auto 2/3 (66%) 0/1 (0%) Mitterbauer 1999 4 CT 4/4 (100%) – Relapse is preceded by 5 to 15 weeks by one [74] step PCR 3 Allo 2/3(66%) – 2 Auto 0/2 (0%) – CT = Chemotherapy Auto = Autologous stem cells transplant Allo=Allogeneic stem cell transplant also has begun to provide important insights into the efficacy of treatment for specific molecular cytogenetic subsets of ALL. Several important issues remain to be answered in carefully controlled trials. If MRD measurements are to be incorporated into clinical trials and used for treatment stratification and evaluation of treatment efficacy, the unresolved issues of technique standardization and quality control must be addressed. The Europe Against Cancer (EAC) and BIOMED initiatives have resulted in the development of standardized and validated method- ology for quantitative PCR analysis in order to permit accurate comparison of MRD data [46]. Adoption of this approach in future trials and standardization of methodologies for flow cytometric MRD studies will be essential to accurately evaluate data from different clinical trials, and to help to answer important questions that remain including: (1) what level of MRD is clinically important; (2) when are the critical treatment time-points for MRD evaluation; (3) will MRD-based treatment intervention improve outcome. Finally, any MRD result must be interpreted in the context of the treatment ad-
Page 1 and 2:
E.H. Estey · S.H. Faderl · H. M.
Page 3 and 4:
E. H. Estey Department of Leukemia
Page 5 and 6:
VI Table of Contents 14 Philadelphi
Page 7 and 8:
VIII Contributors S. H. Faderl Depa
Page 9 and 10:
X Contributors D. Wartenberg Depart
Page 11 and 12:
Therapy of AML Elihu Estey Contents
Page 13 and 14:
a 1.2 · Standard Therapy 3 Table 1
Page 15 and 16:
a 1.2 · Standard Therapy 5 Table 1
Page 17 and 18:
a 1.2 · Standard Therapy 7 tween G
Page 19 and 20:
a 1.2 · Standard Therapy 9 Fig. 1.
Page 21 and 22:
a 1.2 · Standard Therapy 11 of tre
Page 23 and 24:
a 1.2 · Standard Therapy 13 Table
Page 25 and 26:
a 1.2 · Standard Therapy 15 permit
Page 27 and 28:
a References 17 19. Care RS, Valk P
Page 29 and 30:
a References 19 6-thioguanine in th
Page 31 and 32:
Acute Myeloid Leukemia: Epidemiolog
Page 33 and 34:
a 3.1 · Epidemiology 49 3.1.4 Gend
Page 35 and 36:
a 3.2 · Etiology 51 part of the in
Page 37 and 38:
a 3.2 · Etiology 53 for the develo
Page 39 and 40:
a References 55 38. Crane MM, Stom
Page 41 and 42:
Relapsed and Refractory Acute Myelo
Page 43 and 44:
a 4.2 · Prognostic Factors in Pati
Page 45 and 46:
a 4.3 · Treatment of Relapsed and
Page 47 and 48:
a 4.4 · Hematopoietic Stem Cell Tr
Page 49 and 50:
a 4.6 · Gemtuzumab Ozogamicin 65 T
Page 51 and 52:
a 4.7 · Relapsed and Refractory Ac
Page 53 and 54:
a 4.7 · Relapsed and Refractory Ac
Page 55 and 56:
a References 71 The ability of immu
Page 57 and 58:
a References 73 39. Vogler WR, McCa
Page 59 and 60:
a References 75 95. Sievers EL, Lar
Page 61 and 62:
Part II - Acute Lymphoblastic Leuke
Page 63 and 64:
78 Chapter 5 · Acute Lymphoblastic
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
Molecular Biology and Genetics Meir
Page 81 and 82:
a 6.3 · Structural Aberrations 97
Page 83 and 84:
a 6.3 · Structural Aberrations 99
Page 85 and 86:
a 6.5 · Molecular Aberrations 101
Page 87 and 88:
a References 103 clear that homozyg
Page 89 and 90:
a References 105 53. Chim CS, Tam C
Page 91 and 92:
a References 107 122. Lennard L, Li
Page 93 and 94:
Diagnosis of Acute Lymphoblastic Le
Page 95 and 96:
a 8.3 · Cytochemistry and Immunoph
Page 97 and 98:
a 8.5 · Cytogenetic and Molecular
Page 99 and 100:
a 8.5 · Cytogenetic and Molecular
Page 101 and 102:
a References 127 including the reti
Page 103 and 104:
a References 129 47. Kita K, Shirak
Page 105 and 106:
Acute Lymphoblastic Leukemia: Clini
Page 107 and 108:
a 7.3 · Diagnosis 111 or neoplasti
Page 109 and 110:
a 7.3 · Diagnosis 113 Fig. 7.2. Hi
Page 111 and 112:
a 7.3 · Diagnosis 115 The vast maj
Page 113 and 114:
a References 117 dren: Biologic bas
Page 115 and 116:
General Approach to the Therapy of
Page 117 and 118:
a 9.3 · New Agents 133 dose methot
Page 119 and 120:
a References 135 4. Gökbuget N, Ho
Page 121 and 122:
138 Chapter 10 · Recent Clinical T
Page 123 and 124:
Page 125 and 126:
Page 127 and 128:
Page 129 and 130:
146 Chapter 11 · Conventional Ther
Page 131 and 132:
Page 133 and 134:
Page 135 and 136:
Page 137 and 138:
Page 139 and 140:
Page 141 and 142:
Page 143 and 144:
ALL Therapy: Review of the MD Ander
Page 145 and 146:
a 12.2 · The Hyper-CVAD Regimen in
Page 147 and 148:
a 12.3 · Subset-Specific Approache
Page 149 and 150:
Treatment of Adult ALL According to
Page 151 and 152:
a 13.2 · Therapy for Younger (15-6
Page 153 and 154:
a 13.3 · Therapy of Ph/BCR-ABL-Pos
Page 155 and 156:
a 13.5 · Prognostic Factors 173 13
Page 157 and 158:
a References 175 Only patients with
Page 159 and 160:
Philadelphia Chromosome-Positive Ac
Page 161 and 162:
a 14.2 · Molecular Biology of the
Page 163 and 164:
a 14.3 · Treatment of Ph+ ALL 181
Page 165 and 166:
a 14.4 · Hematopoietic Stem Cell T
Page 167 and 168:
a References 185 2. Kurzrock R, Sht
Page 169 and 170:
a References 187 56. Mori T, Manabe
Page 171 and 172:
a References 189 acute lymphoblasti
Page 173 and 174:
192 Chapter 15 · Burkitt’s Acute
Page 175 and 176:
Page 177 and 178:
Page 179 and 180:
Page 181 and 182:
Page 183 and 184:
Page 185 and 186:
204 Chapter 16 · Treatment of Lymp
Page 187 and 188: 206 Chapter 16 · Treatment of Lymp
Page 197 and 198: 216 Chapter 17 · The Role of Allog
Page 211 and 212: 230 Chapter 18 · The Role of Autol
Page 219 and 220: 238 Chapter 19 · Novel Therapies i
Page 229 and 230: 248 Chapter 20 · Minimal Residual
Page 237: 256 Chapter 20 · Minimal Residual
Page 245 and 246: 264 Chapter 21 · Central Nervous S
Page 257 and 258: 276 Chapter 22 · Relapsed Acute Ly
Page 259 and 260: 278 Chapter 22 · Relapsed Acute Ly
Page 261 and 262: Emergencies in Acute Lymphoblastic
Page 263 and 264: a 23.5 · Hyperleukocytosis 283 LA
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
show all

Acute Leukemias - Republican Scientific Medical Library

Create successful ePaper yourself

Delete template?

Save as template?