Acute Leukemias - Republican Scientific Medical Library

More documents

Recommendations

Info

a 19.2 · New Chemotherapy Agents 241 free survival and overall survival [31]. Use of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) or 5-azacytidine may thus provide therapeutic benefit for patients with a defined methylator phenotype. Although experience with these agents in ALL remains sparse, understanding defined genetic and epigenetic changes in adult ALL may offer another dominant molecular mechanism whose targeting may lead to risk-adapted therapies. 19.2.4 Signal Transduction Inhibitors Ph-positive ALL is the most common subtype in adult ALL and has historically been associated with one of the worst outcomes to even intense-dose multiagent chemotherapy regimens [32]. Ph-positive leukemic blasts are characterized by expression of BCR-ABL tyrosine kinases of either 210 kD (p210) or 190 kD (190) as a consequence of the reciprocal translocation between the long arms of chromosomes 9 (harboring the ABL gene) and 22 (BCR). Whereas p210 occurs most commonly in chronic myeloid leukemia (CML), p190 is more frequently expressed in Ph-positive acute leukemias and is also a more active tyrosine kinase activity than p210. Imatinib mesylate (Gleevec) is a small molecule with potent antiproliferative activity against BCR- ABL cell lines in vitro at submicromolar concentrations that are easily achievable clinically. Although imatinib has made its biggest impact in the treatment of patients with CML, p190- and p210-expressing cells are equally sensitive, making Ph-positive ALL a suitable target as well. Although single-agent imatinib is active in Ph-positive ALL, almost all patients will eventually relapse and progress so that major efforts are being invested in combination programs of imatinib with dose-intensive chemotherapy to increase response rates and improve durability of responses. Thomas et al. were the first to combine imatinib with the ALL induction regimen hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with highdose methotrexate and cytarabine) [33]. In a recent update, 25 of 26 patients (96%) with active disease at study entry achieved CR at a median time to response of 21 days [34]. Thirteen of the patients were able to proceed with allogeneic stem cell transplant within a median of 3 months from start of therapy. Molecular responses as assessed by RT-PCR for BCR-ABL occurred in nine of 19 patients. Two-year DFS was 87% with the hyper-CVAD imatinib combination compared with 28% with hyper-CVAD alone in this group of patients. Similar results have been reported by the Japan Adult Leukemia Study Group (JALSG) by Towatari et al. [35]. Of 24 patients with Ph-positive ALL, all but one (96%) achieved CR after a single course of induction therapy. PCR testing was negative in almost 80% of patients during follow up. Fifteen patients (63%) were able to proceed to an allogeneic stem cell transplant. Ottmann et al. compared the efficacy of imatinib in Ph-positive ALL when given either intermittently between chemotherapy courses or concurrently [36]. Concurrent administration achieved higher CR rates (96 vs. 58%) and more profound decreases of BCR-ABL levels by PCR testing. More potent second-generation tyrosine kinase inhibitors such as nilotinib and dasatinib have recently entered clinical trials [37]. Both agents proved more potent in proliferation assays than imatinib and also showed activity against imatinib-resistant cell lines. The role of new kinase inhibitors in Ph-positive ALL is currently investigated in clinical trials. 19.2.5 Monoclonal Antibody Therapy Monoclonal antibody therapy has emerged as one of the most effective additions to the therapy of hematologic malignancies including the acute leukemias. The attraction of monoclonal antibodies is based on two characteristics: (1) selectivity of the tumor target by virtue of expression of more or less tumor-specific cell surface antigens; and (2) different mechanisms of actions compared to more traditional cytotoxic chemotherapy involving elements of the complement system, human effector functions, and most likely intracellular signaling pathways leading to apoptotic cell death. ALL blasts express several antigens that can serve as therapeutic targets including CD19, CD20, CD33, or CD52 [38]. Rituximab is an anti-CD20 directed chimeric monoclonal antibody that has been developed for the therapy of relapsed and refractory indolent NHL. Expression of CD20 is detected in 35% of adult ALL, particularly in elderly patients and has been associated with a worse prognosis [39]. Expression is higher in ALL subsets; up to 55% in Ph-positive ALL and almost ubiquitous in mature B ALL (Burkitt). Combination of rituximab
242 Chapter 19 · Novel Therapies in <strong>Acute</strong> Lymphoblastic Leukemia with induction and consolidation regimens in CD20positive ALL has been explored. Thomas et al. reported their experience with Hyper-CVAD plus rituximab in patients with Burkitt and Burkitt-like leukemia and lymphoma [40]. The CR rate among 22 evaluable non- HIV patients was 95% with no induction deaths occurring in this group. With a median follow up of 18 months, only two patients relapsed. Historical experience of hyper-CVAD alone in mature B ALL showed a CR rate of 81% with 3-year survival rates of between 17% (patients older than 60 years) and 77% (patients younger than 60 years). Rituximab has also been reported to induce molecular remissions in the setting of minimal residual disease in ALL [41]. Alemtuzumab is a humanized monoclonal antibody recognizing CD52. CD52 expression is highest on T and B lymphocytes and most frequently found in chronic lymphoproliferative disorders. Alemtuzumab has established activity in chronic lymphocytic leukemia, prolymphocytic, and other T-cell NHL. CD52 is also detected in 30–50% of ALL blasts. Experience in ALL is limited. Anecdotal reports do not support its use as single agent in relapsed and refractory disease [42]. Alemtuzumab is currently investigated as part of intense induction/consolidation programs and in combination with hyper-CVAD in aggressive T-cell malignancies including T-cell ALL. CD19 is expressed on a large proportion of ALL blasts in most patients with B-lineage disease, and several antibodies targeting CD19 have been developed and are investigated in clinical trials. The antitumor activity of CD19 by itself is weak, but can be enhanced by conjugation with other components. Ricin is a plant toxin with potent antiribosomal activity in vitro. When conjugated as blocked ricin to CD19 (anti-B4 blocked ricin), enhanced cytotoxic activity in lymphoid malignancies has been demonstrated [43]. In a small study of relapsed childhood ALL, biologic activity (reduction in blast percentage) was observed in five of 19 patients, although no objective responses occurred. The CALGB used anti-B4 blocked ricin in B-lineage ALL after induction of residual disease [44]. Although antibody administration was feasible as part of a complex induction and consolidation regimen, no benefit could be proven with respect to remission duration or minimal residual disease levels as assessed by PCR. Experience with other conjugates (e.g., the tyrosine kinase inhibitor genistein, pokeweed antiviral protein immunotoxin) suggest antitumor activity in small studies, but experience remains limited. 19.2.6 Other Agents 19.2.6.1 Pegylated Asparaginase L-asparaginase has been an important component of ALL therapy for many decades. Asparaginase depletes external sources of asparagine, which ALL blasts require for survival, as they are unable to synthesize asparagine. However, native asparaginase has been problematic for two reasons: (1) need for frequent injections; and (2) immunogenicity that can result in anaphylactic reactions or development of neutralizing antibodies with rapid clearance and short plasma half-lives of asparaginase [45]. To overcome these shortcomings, E. coli asparaginase has been covalently linked to mono-methoxy-polyethylene glycol, rendering native asparaginase less immunogenic and extending its plasma half-life to up to 6 days (5–9 times longer), enabling up to biweekly administrations and thus making therapy more convenient for patients. When 144 children with ALL relapse were randomized to receive PEG-asparaginase either weekly or biweekly, there was, however, a significant difference in CR rate favoring weekly administration (97 vs. 82%, p=0.003) [46]. The CR rate was significantly associated with higher levels of asparaginase, which in turn correlated to low antibody titers. Except for infectious complications, other toxicities including hypersensitivity (4%) were infrequent. A Children’s Cancer Group study conducted a randomized comparison of native E. coli asparaginase and PEG asparaginase in children with newly diagnosed ALL as part of induction and delayed intensification [47]. The PEG asparaginase group more rapidly cleared lymphoblasts from early marrow samples and developed less frequently antibodies, which were associated with low asparaginase activity in the native arm. No difference was noted in event-free survival. A recent study in 28 children with relapsed ALL confirmed the pharmacokinetic advantages of PEG asparaginase, which are characterized by high levels of asparaginase activity in serum and CSF and consequently effective asparagine depletion [48]. Limited experience with PEG asparaginase is available in adult ALL patients. 19.2.6.2 Forodesine (BCX-1777) Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolytic cleavage of purine ribonu-
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 185 and 186: 204 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 221: 240 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 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?