Acute Leukemias - Republican Scientific Medical Library

More documents

Recommendations

Info

a 18.5 · Novel Transplant Approaches 233 (12 Gy) in 50 advanced leukemia patients, including 11 with ALL, undergoing allogeneic or autologous SCT. All patients achieved primary engraftment. After a median follow-up of 11 months, 28/50 (56%) patients were in CR, nine (5%) patients relapsed, and 13 (7%) died from treatment-related causes [29]. The ultimate benefits of this approach with respect to safety and improvements in survival will be defined by Phase II studies for patients with ALL. Nonradiation containing regimens, most commonly busulfan and cyclophosphamide, have been investigated in hopes of decreasing radiation-related complications. Fractionated TBI/etoposide was tested against busulfan/cyclophosphamide in a prospective, randomized study conducted by the Southwest Oncology Group (SWOG 8612). One hundred twenty-two patients with leukemia beyond CR1 received either fractionated TBI/ etoposide or busulfan/cyclophosphamide in preparation for SCT. One hundred fourteen (93%) proceeded to SCT. All patients received cyclosporine and prednisone for posttransplant immunosuppression. There was no significant difference with respect to toxicity, incidence of acute GVHD, overall survival, or DFS between the two groups. The leading cause for treatment failure was leukemic relapse (39%) [30]. Furthermore, retrospective analysis of registry data from the International Bone Marrow Transplant Registry (IBMTR) shows similar rates for LFS and relapse when busulfan/cyclophosphamide is compared to cyclophosphamide/TBI [31]. Careful comparisons of the incidence of second malignancies with each of these regimens have not been made but may have important consequences. Thus, a variety of preparative regimens can be used, but leukemic relapse remains the most significant factor affecting DFS. 18.4.3 Ex Vivo Purging One major disadvantage of autologous SCT is autograft contamination leading to an increased rate of relapse. Ex vivo purging methods were developed to decrease the residual leukemic burden of the graft. Pharmacological agents include 4-hydroperoxycyclophosphamide (4- HC), mafosfamide, and edelfosine. One major concern regarding chemical purging is the potential toxic effect on normal progenitor cells [32]. In efforts to overcome this toxicity, some investigators have tested the simultaneous administration of chemoprotectant agents such as amifostine or adenosine triphosphate [33, 34]. Immunological methods of purging rely on MoAbs combined with immunotoxins [35], exposed to complement [27, 36–38], or combined with an iron-bound antibody followed by a magnetic depletion [39]. It is difficult to make any conclusions regarding the efficacy of a particular purging method based on results from multiple, single-center experiences using a variety of purging methods. Generally, immunological purging methods are able to eliminate 2–4.5 logs of leukemia cells. Between 0 and 84% of mononuclear cells are lost during the purging process; between 34 and 96% of CD34 cells are recovered after purging [27]. Although purging with monoclonal antibodies does not typically impair hematologic recovery after transplant, some studies have noted a delay in engraftment [40]. Ex vivo purging of the autograft with anti-sense oligodeoxynucleotide (ODN) or ribonucleotide interference (RNA-I) methods are still largely in preclinical phases but have great potential for certain subtypes of ALL. These methods target a specific mRNA or RNA sequence, and can effectively block the production of a protein; thus, they may be very effective therapy for leukemogenesis that is driven by a specific protein, such as in t(9;22)(q34;q11) ALL. Gewirtz et al. used ODN directed against the c-myb proto-oncogene to purge autografts of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) patients who were not eligible to receive allogeneic SCT (chronic phase, n=20; accelerated phase, n=5) [41]. Autografts were purged ex vivo with ODN for either 24 or 72 h. After purging, Myb mRNA levels declined substantially in approximately 50% of patients. However, cytogenetic response post transplant was mixed in this small pilot study, raising the issue of overall clinical efficacy. Still, the study established the feasibility of ex vivo purging with antisense ODN, and may lead to the development of more effective antisense ODN targeted against a variety of proteins. 18.5 Novel Transplant Approaches 18.5.1 Maintenance Therapy Post-SCT Although the concept of maintenance therapy is established for the chemotherapy treatment of ALL, its use post transplant is not defined. Powles et al. reported on the use of chemotherapy after autologous SCT to prolong DFS. From July 1984 to December 1998, 77 adult
234 Chapter 18 · The Role of Autologous Stem Cell Transplantation in the Management of <strong>Acute</strong> Lymphoblastic Leukemia in Adults ALL patients received an autologous transplant in CR1 at the Royal Marsden Hospital. The preparative regimen consisted of melphalan and total body irradiation until December 1992; subsequently, patients received highdose melphalan alone. Patients were scheduled to receive 6-mercaptopurine (71%), methotrexate (57%), and/or vincristine and prednisone (38%) for 2 years after the transplant. The median time to relapse posttransplant was 13 months. The cumulative incidence of relapse at 10 years was 42% (95% CI, 31–55%). The 10year probability of DFS was 50% (95% CI, 38–62%). Age > 30 years, longer than 4 weeks to attain CR, and high risk karyotype [t(9;22)(q34;q11) and t(4;11) (q21;q23)] were adverse features. Risk stratification using these features identified three prognostic risk groups with 0 (47%), 1 (36%), or 2 (17%) adverse features. The respective 10-year cumulative incidences of relapse were 20, 48, and 85% (p < 0.001), and the probabilities of DFS were 72, 41, and 10% (p = 0.003). Patients who received two or three maintenance drugs had a lower relapse rate than those who received only 0 or 1. Posttransplant maintenance therapy offered a benefit for low and standard risk patients, but not those with high-risk disease [42]. 18.5.2 Targeted Therapies: Imatinib Mesylate The most exciting recent development in the treatment of the t(9;22)(q34;q11), Ph+ subtype of ALL has been the promising early results observed with imatinib, a molecule specifically targeted to the BCR/ABL tyrosine kinase that is overexpressed as a result of the t(9;22) (q34;q11) in CML and Ph+ ALL. Imatinib is a specific inhibitor of the abl protein tyrosine kinase that has demonstrated remarkable targeted therapeutic efficacy in patients with the CML and ALL with increased bcr/abl activity [43]. The Cancer and Leukemia Group B (CALGB), in combination with the Southwest Oncology Group (SWOG) have recently initiated a Phase II trial of sequential chemotherapy, imatinib, and allogeneic or auto-SCT for adults with newly diagnosed Ph+ ALL. The primary objectives of this study will be to determine the ability of imatinib to produce a complete molecular response following sequential chemotherapy, imatinib, and transplantation, and to determine the ability of imatinib to prolong DFS and OS in this high-risk group of patients. The ongoing ECOG2993/ UKALL 12 protocol for Ph+ ALL patients follows a similar strategy [44]. The results of these trials are eagerly anticipated. 18.5.3 Immunotherapy In an attempt to induce an immunological response similar to GVL in allogeneic SCT, immunomodulators, such as interleukin-2 (IL-2), have been tried without success in the autologous SCT setting. Blaise, et al. conducted a prospective, randomized study to investigate the efficacy of IL-2 after autologous BMT for acute leukemia in CR1. One hundred thirty patients were enrolled (ALL, n=52). Analysis was based on an intent to treat, and 59% of patients randomized to IL-2 started the drug after a median of 68 days post transplant, and received 77% of the scheduled dose. With a median follow-up of 7 years, OS and LFS were not statistically different between the two study groups [45]. In vivo and ex vivo purging with MoAbs directed against surface antigens expressed by leukemic blasts, such as CD20 and CD52, are underway in many clinical trials, and results are eagerly anticipated. Finally, active immunotherapy using dendritic cells (DCs) loaded with tumor-associated antigens to induce specific T-cell immunity is a potentially effective approach that is still in early development. Rijke, et al. investigated the use of HB-1 antigen as an autologous T-cell vaccine target, based on their previous studies that indicated HB-1 is a B-cell lineage-specific antigen that is recognized by donor-derived cytotoxic T lymphocytes (CTLs) on allogeneic B-ALL tumor cells. They demonstrated that HB-1 induces both helper and cytotoxic T-cell responses by in vitro studies [46]. This approach now needs to be evaluated in the in vivo setting. 18.6 Conclusion In conclusion, transplantation is an effective modality in the treatment of ALL. In patients with high-risk ALL, multiple randomized trials have demonstrated the tremendous therapeutic benefit for early allogeneic SCT. However, in patients without an appropriate HLA donor, autologous SCT may be a reasonable approach to extend DFS for those in remission. The leukemic burden pretransplant will affect disease outcome, and randomized, prospective studies are necessary to deter-
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 213: 232 Chapter 18 · The Role of Autol
Page 217 and 218: 236 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 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?