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a 17.5 · Factors Influencing Transplant Outcome 221 transplant immunosuppression. There was no significant difference with respect to toxicity, incidence of acute GVHD, OS, or DFS between the two groups. The leading cause for treatment failure was leukemic relapse (39%) [56]. 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 TBI/cyclophosphamide [49]. The addition of monoclonal antibodies to the transplant conditioning regimen is another method of developing potentially more effective, and less toxic, regimens. Antibody therapy is generally considered to be an option when the target antigen is expressed on at least 30% of the targeted cells [50]. ALL blasts express a variety of B- or T-cell differentiation antigens, such as CD19, CD20, CD22, CD33, and CD52, which can serve as targets for directed therapy [50]. The greatest clinical data has been gathered for rituximab, a chimeric MoAb directed against CD20, which has demonstrated efficacy in patients with non-Hodgkin’s lymphoma. At the MD Anderson Cancer Center, rituximab has been incorporated in both the upfront induction regimen for ALL patients who present with CD20 positive disease, as well as in the transplant conditioning regimen for these patients. Preliminary results for rituximab combined with hyper-CVAD for induction therapy have been favorable (Thomas, abstract). The transplant protocol utilizing rituximab, cyclophosphamide, and TBI is still in the process of patient accrual, but no excess adverse results have been noted thus far (Khouri, personal communication). CD19 is expressed in a large portion of B-lineage ALL patients, and several antibodies have been developed against the CD19 antigen. Since this antigen readily modulates internally, studies have generally involved anti-CD19 MoAb-based immunotoxins. Preliminary results from small phase I studies suggest that they are feasible as an adjunct to chemotherapy, but that efficacy for MoAbs as monotherapy is limited, especially in the setting of overt relapse or rapidly progressive disease [51, 52]. Campath-1H, a humanized MoAb developed against the CD52 antigen, is particularly interesting since it targets a subset of ALL for disease eradication, as well as a novel method of T-cell depletion to prevent GVHD in the allogeneic transplant setting. The clinical efficacy has been limited in the nontransplant setting [53, 54], but the agent may be potentially more useful with allogeneic SCT. Campath-1H either as an intravenous treatment or for ex vivo purging of the allogeneic cells, is effective to reduce the incidence and severity of graft-vs.-host disease following allogeneic SCT. Novitzky et al. evaluated 13 patients with ALL (eight in CR1) and 37 patients with AML (33 in CR1), who had undergone HLA-identical sibling transplants. The conditioning regimen consisted of TBI/cyclophosphamide. Bone marrow or PBSC were exposed to CAMPATH-1H ex-vivo. Patients received no posttransplant immunosuppression. All but one patient engrafted, and only 22% of all patients developed grade I or II GVHD; there was no severe GVHD. There is concern that the immunosuppressive effect of Campath-1H may inhibit the immune graft-vs.-malignancy effect and 54% (7/13) of the ALL patients in this study relapsed [55]. A study is ongoing at MD Anderson combining Campath-1H with cyclophosphamide and TBI to provide both disease eradication and in vivo Tcell purging in a transplant protocol for CD52+ lymphoid malignancies at MD Anderson Cancer Center. The trial is currently in the process of accruing patients, and preliminary results are promising (Khouri, personal communication). Large, randomized studies will be required to determine whether inclusion of Campath-1H will improve the overall outcome for patients undergoing transplantation for ALL. 17.5.1.3 Nonmyeloablative SCT (NMSCT) Numerous studies have now demonstrated successful donor stem cell engraftment with NMSCT for hematologic and solid organ malignancies. These regimens use reduced doses of chemotherapy +/– low dose TBI as immune suppression to prevent graft rejection and allow development of an immune graft-vs.-malignancy (GVM) effect. GVM appears to be operative against ALL; the major evidence being a reduced rate of relapse in patients who have GVHD. However, ALL appears less effected by GVM than the other major forms of leukemia and the role of NMSCT requires further evaluation. The major benefit of NMSCT is a lower risk of drug toxicity and treatment-related morbidity and mortality, which is most relevant to older or debilitated patients unable to tolerate ablative preparative regimens. This option would be particularly attractive for patients with Ph+ ALL where the majority of patients are older than 50 years.
222 Chapter 17 · The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult <strong>Acute</strong> Lymphoblastic Leukemia (ALL) Martino et al. reported on the largest published cohort of adult ALL patients receiving NMSCT [56]. He analyzed the results of 27 patients with high-risk ALL that were included in four prospective studies. Similar to other reduced-intensity transplant series, these were older patients with advanced disease. The median age was 50 years; 23 (85%) patients were beyond CR1, 44% were chemorefractory, and 41% were Ph+. Donors were mismatched related donors or volunteer unrelated donors in 12 cases (44%). The incidence of grades II-IV acute GVHD was 48%, and 13 of 18 evaluable patients (72%) developed chronic GVHD. With a median follow-up of 809 days, the incidence of TRM was 23%, the probability of OS was 31%, and the incidence of disease progression was 49% at 2 years. The incidence of disease progression in patients with and without GVHD, 35% and 47%, respectively, approached statistical significance (p = 0.05). The incidence of disease relapse was 33% in patients transplanted in CR compared to 60% in those with overt disease. These observations for NMSCT must be validated in well-defined prospective trials. NMSCT, as an immunotherapeutic approach, is probably most appropriate in patients with low-bulk disease. In this study, and others, a higher relapse rate was observed for patients transplanted with overt disease [57]. Thus, NMSCT does not appear indicated for patients with overt relapsed or resistant ALL. The initial studies appear most promising for older patients transplanted in remission, and the reported OS and TRM rates were quite favorable considering the advanced disease state of the patients and the number of unrelated transplants included in this series. Thus, it is reasonable to enroll older patients (age > 50 years) and those with a high risk of TRM onto prospective studies of NMSCT. Younger allogeneic transplant candidates without major comorbidities, should still receive high dose therapy with ablative preparative regimens, as established effective treatment for ALL. 17.5.2 Source of Stem Cells 17.5.2.1 Bone Marrow vs. Peripheral Blood Stem Cells Bensinger et al. published a prospective, randomized trial comparing bone marrow (BM) to peripheral blood as the source of stem cells. Between March 1996 and July 1999, 172 patients, including 22 with ALL, with a median age of 42 years, were randomly assigned to receive BM or filgrastim-mobilized peripheral blood stem cells (PBSC) from HLA-identical relatives for hematopoietic rescue after dose-intensive chemotherapy. After randomization, patients were stratified according to age and stage of cancer, with roughly equal numbers in the two groups. It was concluded from this study that allogeneic PBSC result in faster engraftment without an increased risk of GVHD (median day to neutrophil recovery defined as > 500/mm 3 , 16 vs. 21, p-value < 0.001; median day to platelet recovery defined as > 20 000/mm 3 , 13 vs. 19, p-value < 0.001). It was also observed that patients who received PBSC had a lower incidence of relapse at 2 years, and higher OS and DFS [55]. While similar subsequent series have confirmed that PBSC result in faster engraftment, a large retrospective analysis from the IBMTR and EBMT showed that the incidence of chronic GVHD was significantly higher with the use of PBSC (65 vs. 53%, p=0.02). In addition, the risk of relapse was not significantly different between these two groups [58]. Thus, a large, multicenter, prospective study was developed to help define the role of PBSC in allogeneic SCT. In this collaborative effort by the BMT-CTN, adult leukemia patients requiring MUD transplantation will be randomized to BM or PBSC donors. Results of this trial are eagerly anticipated. 17.5.2.2 Umbilical Cord Blood (UCB) Recently, UCB transplantation (UCBT) is beginning to emerge as a viable alternative hematopoietic stem cell source for patients who lack an HLA-matched donor. UCBT is less likely to produce severe GVHD compared to bone marrow transplantation, and thus has the advantage of allowing for greater HLA disparity between donor and recipient. Its disadvantage, however, is the significantly lower cell dose in UCB when compared to PBSC or BM (the cell dose in one average UCB unit is 1/10 of a typical BM allograft and 1/100 of a PBSC allograft), predictably resulting in a longer time to engraftment, and potentially greater early posttransplant complications. UCB transplants have had the best results in children where a relatively high cell dose/kg can be administered. There has been a greater risk of complications in adult recipients. More than 500 adults have undergone UCBT worldwide [59–64], mainly for hematologic malignancies. Similar to the pediatric series, the majority of patients
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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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272 Chapter 21 · Central Nervous S
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274 Chapter 21 · Central Nervous S
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276 Chapter 22 · Relapsed Acute Ly
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278 Chapter 22 · Relapsed Acute Ly
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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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