Acute Leukemias - Republican Scientific Medical Library

More documents

Recommendations

Info

a 21.5 · CNS Prophylaxis 267 IT involves the direct injection of drugs into the CSF and is an obvious way to bypass the BBB. Relatively small doses of a drug given by intrathecal injection can achieve high local concentrations, due to the small volume of CSF. Furthermore, because of intrinsically low levels of metabolizing enzymes in the CSF, agents that are subject to rapid metabolism in blood may avoid degradations in the CSF [47]. For example, one of the principal mechanisms of inactivation of cytarabine in the bloodstream is deamination catalyzed by cytidine deaminase. Cytidine deaminase is present at much lower concentration in CSF, which results in an eightfold longer half-life of the drug in CSF than in plasma. In addition, more unbound drug is available to diffuse from CSF to brain tissue because of the very low protein content in the CSF [48]. IT has historically employed methotrexate single agent or methotrexate combined with cytarabine, with or without steroids. Liposomal cytarabine (DepoCyt) is a slow-release formulation of cytarabine that is manufactured by encapsulating the aqueous drug solution in spherical multivesicular particles known as Depo- Foam, which consist of 96% water and 4% biodegradable lipid. A recent trial of intrathecal DepoCyt in children with neoplastic meningitis showed that eight of the 14 assessable patients demonstrated evidence of benefit manifested by prolonged disease stabilization or response [49]. The importance of IT for CNS prophylaxis in adults with ALL was first established in a randomized trial comparing CNS chemo-prophylaxis with cranial irradiation with 2,400 rads plus IT methotrexate versus cranial irradiation alone [8]. Three of 28 evaluable patients (11%) receiving IT had a CNS relapse, compared with 11 of 34 patients (32%) not receiving any prophylaxis. Several chemotherapy agents used systemically may have CNS activity when used at adequate doses. Systemic administration of high-dose cytarabine reaches therapeutic levels in the CSF, which is slowly degraded to ara-U due to the absence of cytidine deaminase in this compartment [45]. Thus, systemic administration of high-dose methotrexate or high-dose cytarabine can effectively eradicate CNS leukemia [50, 51], although there is patient-to-patient variability in the drug concentrations of these agents achieved in the CSF. Systemic administration of dexamethasone and prednisone have been utilized in combination with IT, and have significant antileukemic activity. Dexamethasone is five to six times more potent than prednisone [52]; in addition dexamethasone achieves higher CSF levels and has longer half-life in the CSF than prednisone [53]. Although cytarabine, methotrexate, and steroids (particularly dexamethasone) are the most important systemically administered agents used for CNS prophylaxis, other agents may have some role. Etoposide administered intravenously or as low-dose orally prolonged administration achieves effective concentration in the CSF and may contribute to successful CNS prophylaxis in same pediatric regimens [54]. The oral absorption of 6-mercaptopurine (6-MP) is highly variable. However, prolonged IV infusion can reach therapeutic levels in the CSF and is associated with improved antileukemic activity in vitro [55]. A recent report from Children’s Cancer Group in standardrisk ALL patients compared daily oral versus weekly intravenous 6-MP. The 6-year EFS were similar in both groups. However, patients receiving IV 6-MP had unexplained shorter survival after relapse than oral 6-MP patients [56]. IV administration of L-asparaginase can deplete the CSF of L-asparagine for prolonged periods of time [57, 58]. Pegylated L-asparaginase has a prolonged half-life that may result in high plasma levels of asparaginase, and prolonged asparagine depletion in serum and CSF is achieved [59]. Cranial irradiation has been frequently utilized in patients with high-risk CNS disease [60, 61], but CNS regimens without cranial irradiation have also achieved excellent results [62, 63]. The Pediatric Oncology Group published a clinical study where two different regimens of intrathecal and systemic chemotherapy were used for CNS prophylaxis in children with acute leukemia. The standard regimen (S) consisted on six injections of triple intrathecal chemotherapy (TIC) with methotrexate, hydrocortisone, and cytarabine administered during intensification treatment and at 8-week intervals throughout the maintenance phase for 17 additional doses. The second regimen, standard and methotrexate pulses (SAM), also specified six TIC administrations during intensification, but substituted pulses of intermediatedose parenteral methotrexate (IDM, 1 g/m 2 ) every 8 weeks for the 17 maintenance TIC injections, with a low-dose IT methotrexate boost administered with the first four maintenance IDM pulses. Otherwise, systemic therapy on regimen SAM was identical to regimen S. The 5-year of an isolated CNS relapse was regimen S: good risk 2.8%, and poor risk 7.7%; for the regimen
268 Chapter 21 · Central Nervous System Involvement in Adult <strong>Acute</strong> Lymphocytic Leukemia SAM: good risk 9.6%, and poor risk 12.7%. In poor-risk patients, approximately one third of the isolated CNS relapses occurred before preventive CNS therapy was begun at week 9. Hence, regimen S has provided better CNS preventive therapy for both good- and poor-risk patients (p < 0.001 overall) [62]. Several issues remain debatable: which drugs are the best IT combinations, the preferred schedule of administration, and the use of a risk-oriented strategy. Some of the lessons learned from childhood ALL have been analyzed in an attempt to answer these questions. A risk-oriented approach is clearly indicated. In low-risk childhood ALL patients, IT alone can effectively prevent CNS disease, and this is the preferred method for CNS prophylaxis for this group of patients because of toxicities of cranial irradiation in a growing child [61, 64]. Although the definition of low-risk disease varies, CNS relapse rates in this group are £5% in most studies. For intermediate-risk patients two studies have combined IT with HDCT [65, 66] whereas others combined low-dose (1200 rads) cranial irradiation with IT [61]. Both approaches have similar response rates with long-term CNS disease-free survival (DFS) rates about 90% with or without cranial irradiation. There are few studies regarding CNS prophylaxis in adult ALL and they vary considerably with respect to inclusion criteria, dose of radiation, dose of chemotherapy, and timing of prophylaxis. A summary of selected trials is presented in Table 21.2. Table 21.2. CNS prophylaxis by induction treatment regimen It is clear that at least two modalities are required for adequate prophylaxis. Most trials have used a combination of IT and cranial irradiation. However, an approach combining high-dose IV methotrexate, cytarabine, and dexamethasone in conjunction with 16 doses of IT methotrexate alternating with cytarabine has been reported to greatly reduce the risk of CNS leukemia [5, 67]. Analysis of multiple chemotherapy approaches without cranial irradiation from a single institution was published by Cortes et al. [5]. Patients at low risk for CNS leukemia were given high-dose cytarabine and intermediate-dose methotrexate. Their 5-year CNS event-free rate was 85%, which compares favorably to the historical 65% with no prophylaxis (p = 0.05). Comparatively, for patients with high-risk CNS leukemia who had no prophylaxis, the 5-year CNS eventfree rate was 28%, compared to 67% with HDST, 70% with HDST plus late (at the time of CR) IT, and 98% (at 3-year EFS) with HDST and early (starting with induction chemotherapy) IT [5]. This study emphasizes the importance of early start of prophylaxis (i.e., at the start of induction chemotherapy) and the use of a risk-oriented approach for prophylaxis. In this study risk was determined by the serum LDH level and the percentage of cells in S + G2M phase in the bone marrow. Mature B-cell ALL is by definition associated with high risk for CNS disease. Between 10 to 40% of patients Treatment regimen a CNS prophylaxis Low risk High risk VAD High-dose systemic chemotherapy b High-dose Systemic chemotherapy b Modified VAD High-dose systemic chemotherapy c Hyper-CVAD High-dose systemic e +IT(´ 4) chemotherapy f High-dose systemic c +IT(´22) chemotherapy High-dose systemic e +IT(´ 4) chemotherapy f CNS, central nervous system; high-risk, mature B-cell immunophenotype, or the presence of either elevated serum levels of lactate dehydrogenase or high proliferative index in the bone marrow (i.e., ³ 14% cells in S and G2M phase; all others were low risk); VAD, Vincristine, doxorubicin, and dexamethasone; IT, intrathecal. a IT started in complete response for patients on the modified VAD regimen and during induction for patients on the hyper-CVAD regimen. b High-dose cytosine arabinoside (ara-C) (3 g/m 2 every 12 h for six doses) and moderate dose methotrexate (MTX) (400–1600 mg/m 2 ). c High-dose ara-C (3 g/m 2 every 12 h for six doses). d Ara-C 100 mg weekly ´ 8, then every other week ´ 8, then monthly ´ 6 (22 IT doses in 12 months). e High-dose ara-C (3 g/m 2 every 12 h for four doses) and high-dose MTX (1 g/m 2 ). f MTX 12 mg on day 2, ara-C 100 mg on day 8 with each hyper-CVAD or MTX/ara-C course. High-risk patients received 16 IT doses, low-risk patients received four IT doses.
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:
Page 189 and 190:
Page 191 and 192:
Page 193 and 194:
Page 195 and 196:
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 245 and 246: 264 Chapter 21 · Central Nervous S
Page 247: 266 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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?