Acute Leukemias - Republican Scientific Medical Library

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a 17.3 · Results with Allogeneic Transplantation for High-Risk ALL 217 Table 17.2. Allogeneic transplantation for ALL in CR1 Study No. Med. age (yrs) Preparative GVHD II-IV GVHD3 3-yrs DFS% pts regimen prophylaxis Wingard, 1990 [23] 18 24 (5–36) CY/TBI CSA +/– MP 8 42 Blaise, 1990 [17] 25 22 (4–36) CY/fTBI, ML/fTBI CY/ML/fTBI MR 7 71 Chao, 1991 [18] 53 28 (1–45) Ara-C/CY/TBI CSA +/– MP 6 61 CY/TBI VP-16/TBI MTX +/– MP Doney, 1991 [20] 41 22 (18–50) CY/fTBI or Single dose TBI MR 7 21 (5 yrs) Sutton, 1993 [21] 184 25 (15–44) CY/TBI MR 15 deaths 49.5 (6 yrs) (retrospective review) (majority) Vey, 1994 [22] 29 24 (16–41) CY/TBI CSA/MTX 7 62 (8 yrs) DeWitte, 1994 [19] 22 15–51 CY/TBI CSA NR 58 CY, cyclophosphamide; TBI, total body irradiation; fTBI, fractionated TBI; VP-16, etoposide; MR, multiple regimens; NR, not reported; CSA, cyclosporine; MTX, methotrexate; MP, methylprednisolone. 40 years of age were assigned to allogeneic SCT if they had an HLA-matched 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. The study separately evaluated high- and standard-risk subsets. High-risk was defined as having one or more of the following factors: presence of the Ph chromosome, null ALL, age > 35 years, WBC count > 30´10 9 /L, time to CR >4 weeks. The remaining patients were considered standard risk. This study showed that survival at 10 years was significantly greater for the allogeneic SCT group compared to consolidation chemotherapy (46% SCT vs. 31% chemotherapy, p=0.04). Furthermore, when these groups were stratified into high and standard risk, there was a highly significant benefit for allogeneic SCT in the high-risk subset, but no statistically significant benefit seen for the standard risk subset (high risk: 44% SCT, 11% chemotherapy, p=0.009; standard risk: 49% SCT, 43% chemotherapy, p=0.6) [24, 25]. There was no statistically significant difference in outcome between patients who received autologous SCT versus consolidation chemotherapy (34% SCT, 29% chemotherapy, p=0.6), with no difference detected in either the highor standard-risk subset. The United Kingdom <strong>Medical</strong> Research Council’s (MRC) UKALL XII/Eastern Cooperative Oncology Group (ECOG) E2993 is also conducting a prospective trial to define the role of allogeneic SCT, autologous SCT, and conventional dose 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 [26], 239 patients received an allogeneic SCT (170 Ph–) 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) karyotype, when patients were stratified into
218 Chapter 17 · The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult <strong>Acute</strong> Lymphoblastic Leukemia (ALL) high or standard risk, the difference in EFS becomes more dramatic in the high-risk subset (allogeneic BMT 44% vs. chemotherapy/autologous BMT 26%, p=0.06). In conclusion, both of these large prospective controlled studies determined that allogeneic SCT improved the outcome for adults with high-risk ALL in CR1. 17.3.2 Beyond CR1 There are no data suggesting that durable remissions can be achieved with standard chemotherapy for adults with ALL who fail to achieve an initial complete remission or have recurrent disease. Second complete remissions can often be achieved, but are typically of shorter duration than the initial response. Patients who undergo an allogeneic SCT in CR2 have achieved long-term, leukemia-free survival (LFS) rates between 14% to 43%, as illustrated in Table 17.3 [20, 23, 27–30]. Therefore, if patients are in remission, allogeneic SCT results in greater LFS when compared to chemotherapy. The primary cause of failure is relapse (> 50%). Table 17.3. Allogeneic transplantation for ALL in CR2 Study No. LFS (%) Risk of patients relapse IBMTR, 1989 208 (high 22 (4 yrs) 56 [27] risk) 97 (standard risk) 36 (4 yrs) 49 Barrett, 1989 [28] 391 26 (5 yrs) 52 Wingard, 1990 [23] 36 43 (5 yrs) 26 Doney, 1991 [20] 48 15 (5 yrs) 64 Greinix, 1998 [29] 27 14 (3 yrs) 78 Michallet, 47 30 +/– 8% 44+/– 2000 [30] (5 yrs) 12% 17.3.3 Primary Refractory ALL With current induction regimens, only 5–10% of adults with newly diagnosed ALL fail to achieve remission. These patients often have poor prognostic factors at presentation, and additional attempts at induction chemotherapy are usually of limited benefit. Several studies suggest that patients with an HLA-identical sibling benefit by receiving allogeneic transplantation without undergoing a second attempt at induction therapy [31–33]. In the largest of these studies, 38 patients with ALL failing to achieve remission received HLA-identical sibling transplants. Approximately 35% of these patients with refractory disease became long-term, disease-free survivors. In a retrospective review of patients with primary refractory and relapsed ALL, the records of 314 adults were reviewed for disease outcome at MD Anderson Cancer Center between 1980 and 1997. Allogeneic SCT was performed in 29 patients (13 in salvage and 16 in CR2). The rates for durable CR posttransplant were comparable between the two groups; 5/13 (38%) in the salvage group and 5/16 (31%) in the remission group. Although patient numbers are small and a variety of transplant conditioning regimens were used, these results corroborate the findings of earlier studies, and suggest that allogeneic transplant should be considered for these patients with an otherwise dismal chance of long-term survival [34, 35]. 17.4 Philadelphia Chromosome-Positive ALL Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia is well established to have a very poor prognosis. The recent incorporation of imatinib mesylate into combination chemotherapy has been a major development. Imatinib is a highly effective, targeted therapy directed against the BCR/ABL tyrosine kinase that is overexpressed as a result of the t(9;22) (q34;q11) in chronic myeloid leukemia and Ph+ ALL [34]. The rapid initial response to therapy and minimal side effects make imatinib an ideal drug for incorporation into clinical trials for treatment of newly diagnosed Ph+ ALL. In a study by Thomas et al., 20 patients with newly diagnosed Ph+ ALL received concurrent hyper- CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone) and imatinib at the 400 mg dose. All patients achieved CR. Ten patients received allogeneic SCT in first CR within a median of 3.5 months, with
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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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268 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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