Acute Leukemias - Republican Scientific Medical Library

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a 18.3 · Comparison of Autologous SCT with Allogeneic SCT and Chemotherapy 231 protocol to assess the role of allogeneic SCT and autologous SCT in adult ALL. After exclusions, 572 patients were analyzed. The median age of patients entered onto this trial was 33 years, with 10-year follow-up. Patients received induction chemotherapy with cyclophosphamide, vincristine, prednisone, and one of two anthracyclines. Central nervous system (CNS) prophylaxis was administered. Four hundred thirty-six patients (76%) achieved complete remission. After CR was achieved, patients older than 50 years received postremission chemotherapy. Patients between 15 and 40 years of age were assigned to the allogeneic SCT arm if they had an HLAmatched sibling donor. Patients between ages 40 and 50, and those under the age of 40 without a matched sibling donor, were further randomized to consolidation chemotherapy or autologous SCT using bone marrow purged with antibodies or mafosfamide. Consolidation chemotherapy consisted of three monthly courses of daunorubicin or zorubicin, Ara-C, and asparaginase followed by long-term maintenance therapy. The transplant preparative regimen consisted of TBI and cyclophosphamide. There was no statistically significant difference in outcome between patients who received autologous SCT vs. consolidation chemotherapy (34% SCT, 29% chemotherapy, p=0.6). After stratification into high and standard risk, there was still no statistical difference between these two groups. At 10 years, only allogeneic SCT resulted in significantly greater survival among all risk groups (46% allogeneic SCT, 31% chemotherapy, p=0.04), and even more marked among the high-risk subset (high-risk: 44% allogeneic SCT, 11% chemotherapy, p = 0.009; standard-risk: 49% SCT, 43% chemotherapy, p=0.6) [8, 14]. The United Kingdom Medical Research Council’s (MRC) UKALL XII/Eastern Cooperative Oncology Group (ECOG) E2993 is an on-going international effort to prospectively define the role of allogeneic SCT, autologous SCT, and chemotherapy in adult patients with ALL in CR1. Initiated in 1993, over 1200 patients have been enrolled to date. All patients received two phases of induction therapy, and continued to allogeneic SCT if they achieved CR and had a histocompatible donor. The remaining patients were randomized to standard consolidation/maintenance therapy for 2.5 years vs. a single autologous SCT. The conditioning regimen for both allogeneic and autologous transplants was fractionated TBI (1320 cGy) and VP-16 (60 mg/kg). Based on the data presented in an abstract in 2001 [9], 239 patients received an allogeneic SCT and 291 patients received chemotherapy or autologous SCT. The overall event-free survival (EFS) for the allogeneic SCT group was 54 vs. 34% (p = 0.04) for the chemotherapy or autologous BMT group. Excluding the t(9;22)(q34;q11) karyotype, when patients were stratified into high or standard risk, the difference in EFS becomes more dramatic in the high-risk subset (allogeneic BMT 44% vs. chemo/ autologous BMT 26%, p =0.06). In conclusion, both of these large series defined in a prospective manner the efficacy of allogeneic SCT over chemotherapy or autologous SCT for adults with high-risk ALL in CR1. However, as stated previously, not all patients have an available HLA-appropriate donor. Weisdorf et al. reported the results of 337 ALL patients (121 adults; 216 children) who received matched unrelated donor (MUD) SCT and compared them to 214 patients (54 adults; 160 children) who underwent autologous SCT between 1987 and 1993. For those transplanted in CR1, autologous SCT yielded a significantly higher DFS (42% autologous SCT vs. 32% MUD, p =0.03). In contrast, for those transplanted in CR2, MUD SCT yielded a better DFS (20% autologous SCT vs. 42% MUD, p=0.02). The worse outcome with autologous SCT in CR2 likely reflects the increased relapse hazard in the advanced leukemia group. When the data were analyzed separately for children and adults in CR2, MUD SCT still yielded a higher DFS when compared to autologous SCT (adults, MUD 42%+/– 22% vs. autologous SCT 0%, p=0.006) [15]. These results were corroborated by a study performed by the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation (EBMT). Data from ALL patients undergoing SCT between January 1987 and December 1994 was analyzed [16]. One hundred eighteen patients with a median age of 14 years received MUD SCT; 236 patients with a median age of 16 received autologous SCT. Disease status ranged from CR1 to CR3. There were no significant differences in the 2-year leukemia free survival (LFS) for MUD SCT vs. autologous SCT in this retrospective analysis of ALL patients matched for diagnosis, age, stage of disease, and year of transplantation (39% MUD, 32% auto). However, relapse was significantly lower in the MUD SCT group (MUD 32% vs. auto 61%, p
232 Chapter 18 · The Role of Autologous Stem Cell Transplantation in the Management of Acute Lymphoblastic Leukemia in Adults ported on 164 patients (ALL, n=84) who received a partially matched related donor transplant (PMRDT) at the Division of Transplantation Medicine, South Carolina Cancer Center between February 1993 and December 1999, and compared outcomes to 131 patients (ALL, n=81) who had received an autologous SCT at the Royal Marsden Hospital, Surrey, UK between April 1984 and November 1999 [13]. For PMRDT, patients were prepared with cyclophosphamide/TBI/methylprednisolone ± anti-thymocyte globulin (ATG), followed by cyclosporine/methylprednisolone/ATG for GVHD prophylaxis. In the autologous SCT group, patients received a variety of TBI- or busulfan-based preparative regimens. All PMRDT patients received Tcell-depleted bone marrow (BM). In the autologous SCT group, 114 patients received BM and 17 patients received peripheral blood stem cells (PBSC). Marrow was purged with anti-CD52 monoclonal antibody (MoAb) in 13 autologous SCT patients. The 5-year cumulative incidence of TRM was 52% after PMRDT vs. 16% after autologous SCT (p < 0.0001). The 5-year cumulative incidence of relapse was 32% after PMRDT vs. 54% after autologous SCT (p = 0.006). The actuarial unadjusted 5-year DFS was 16% after PMRDT vs. 30% after autologous SCT (p = 0.006). In conclusion, these findings suggest that the increased risk of relapse after autologous SCT is offset by the increased TRM of PMRDT, and therefore, autologous SCT is a superior option for patients with advanced leukemia who do not have an HLA-identical related donor. These conclusions are limited by the retrospective nature of this study, and the heterogeneity in the therapeutic approach of the two different institutions. 18.4 Factors Influencing Transplant Outcome 18.4.1 Source of Stem Cells Powles et al. established the superiority of PBSC in shortening the time to hematopoietic cell recovery [17]. This is especially important since purging methods can delay hematopoietic recovery. In addition, a study by Atta, et al. demonstrated differences in leukemic contamination between PBSC and BM grafts [18]. In 40 consecutive BCR/ABL positive patients, 32% of unpurged PBSC were already BCR/ABL negative as compared to unpurged BM. Furthermore, the positive PBSC were contaminated at a lower level as compared to the BM grafts. However, other studies have not detected a difference in graft contamination, perhaps due to differences in methodology [19]. 18.4.2 Preparative Regimens Several different preparative regimens for autologous SCT have been described in attempts to decrease TRM and improve DFS. The most widely used regimen is the combination of TBI and cyclophosphamide developed by Donnall Thomas and colleagues in the 1970s. The TBI, ranging between 1200 and 1350 cGy, can be administered as a single dose, or fractionated over 3– 5 days. A comparative analysis of fractionated-dose vs. single-dose TBI in adult ALL patients showed a significantly higher transplant-related mortality (TRM) in the single-dose group (p = 0.017), but an increase in the relapse rate of the fractionated-dose group; consequently, there were no differences in the overall LFS between the two groups [20]. A number of different chemotherapy agents, including high-dose cytarabine, vincristine, melphalan, etoposide, and/or anthracyclines have been combined with TBI with no clear advantage for any specific combination [21–24]. In attempts to intensify the antileukemic effect of the preparative regimen, the addition of a third agent to the classic cyclophosphamide/TBI combination has also been investigated. However, in contrast to results obtained with children [25, 26], the intensification of the preparative regimen improved DFS at the expense of increased TRM in adults, thereby, ultimately not improving OS [27]. Thus, novel methods to allow selective delivery of therapy to sites of leukemia without increasing systemic toxicity are currently under investigation. Radio-immunoconjugated MoAbs with iodine-131 or yttrium-90 have already been used in advanced lymphoma patients with promising results [28]. A Phase I transplant trial using 131 I-labeled anti-CD45 antibody combined with cyclophosphamide/TBI was conducted in patients with advanced hematologic malignancies. The dose-limiting toxicity was grade III/IV mucositis. Nine patients with ALL (relapsed/refractory, n=5; CR2 or CR3, n=4) received allogeneic (n = 6) or autologous (n = 3) transplants using this preparative regimen; three patients were disease-free 19, 54, and 66 months posttransplant. A more recent study evaluated the feasibility of using 188 rhenium ( 188 Re)-labeled anti-CD66 in combination with standard high dose chemotherapy/TBI
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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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Page 261 and 262: Emergencies in Acute Lymphoblastic
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a 23.5 · Hyperleukocytosis 283 LA
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a 23.9 · Neurological Complication
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a References 287 29. Hingorani AD,
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Subject Index A aberrant methylatio
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a Subject Index 291 CREB, see enhan
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a Subject Index 293 MUD, see matche
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