Acute Leukemias - Republican Scientific Medical Library

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a 11.8 · Results of Stem Cell Transplantation in LALA Study Group 151 Fig. 11.5. DFS according to genetic randomization in the LALA-94 trial. was 46% with allogeneic SCT vs. 31% with chemotherapy or autologous SCT (p = 0.04). In the high-risk group (including Philadelphia-positive ALL), survival rates at 10 years were 44% in the allogeneic SCT group vs. only 11% in the control arm (p =0.009). In the standard-risk group, the corresponding numbers were 49% and 39%, respectively. These results supported the value of allogeneic SCT in first CR in patients with high-risk ALL [18]. Actually, non-Philadelphia-positive high-risk ALL represents the majority of ALL cases. In the LALA-94 trial, allogeneic SCT did better than the other postremission therapeutic strategies in terms of DFS in Philadelphia-negative high-risk patients using the results of the HLA typing as a random allocation (5-year DFS: 45% vs. 23%; p=0.007) (Fig. 11.5) [24]. Furthermore, allogeneic SCT appeared definitively of benefit to Philadelphia chromosome-positive ALL [25], t(4;11) ALL, and t(1;19) ALL [33]. These results, together with recent data showing no difference in related compared with unrelated transplant in first CR [34], suggest the feasibility of using matched unrelated donor SCT in future clinical trials for those patients in absence of a sibling donor. Our results confirmed those of the <strong>Medical</strong> Research Council UKALL XII/Eastern Cooperative Oncology Group E2993 trial, in which data suggested that allogeneic SCT was beneficial in first CR, regardless of the risk group, challenging the current approach of restrict- ing allogeneic SCT to high-risk ALL patients in first CR only [35]. 11.8.2 Autologous Stem Cell Transplantation In the LALA-87 trial, based on an intent-to-treat analysis, survival at 10 years was 34% in the autologous SCT arm vs. 29% in the chemotherapy arm (p = NS). Sixtysix percent of patients actually received transplantation. After stratification according to standard-risk and highrisk criteria, the difference was still not significant. In high-risk ALL (including Philadelphia-positive ALL), the OS rate at 10 years was 10% for the autologous SCT arm vs. 16% for the chemotherapy arm. In standard-risk ALL, the 10-year OS rate was 49% in the autologous SCT arm and 40% in the chemotherapy arm [18]. In the LALA-94 trial, autologous SCT and chemotherapy resulted in high-risk ALL in comparable median DFS (15.2 vs. 11 months) with 3-year DFS of 39% and 24%, respectively (p = NS). However, there were some flaws in all studies: the number of patients in each arm was small, and some patients allocated to the transplantation group actually did not undergo transplantation. In a retrospective study including adult patients randomized in the three successive trials7LALA-85, LALA-87, and LALA-947autologous SCT did not show superiority over chemotherapy in high-risk ALL patients, although a different pattern of relapse was ob
152 Chapter 11 · Conventional Therapy in Adult <strong>Acute</strong> Lymphoblastic Leukemia: Review of the LALA Program served after autologous SCT with fewer late relapses [36]. The use of autologous SCT in first remission was, however, not advocated. 11.9 Prognostic Factors The majority of adults with ALL now achieve CR. Unfortunately, despite these achievements, the majority of these patients still relapse. One way of approaching this challenge is to examine options for postremission therapy based on the prognostic factors. Different classifications have been proposed [13, 16, 37], identifying roughly three risk groups: a standard-risk group that contains patients with B- or T-lineage ALL who have no adverse cytogenetics [absence of t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, or t(1;19)/E2A-PBX1], are under age 30, present with white blood cell counts of less than 30´10 9 /l, and achieve CR in less than 4 to 6 weeks; a poor-risk group that contains patients with adverse cytogenetics, present with WBC counts of more than 100 ´10 9 /l, or who achieve late CR, and patients aged more than 60 years; and an intermediate-risk group that contains patients with prognostic characteristics of neither the standard-risk nor the poor-risk group. These prognostic factors were also considered in the LALA trials, in which other factors were identified. In the LALA-87 trial, T-cell lineage ALL had a more favorable outcome than B-cell lineage ALL [38]. T-ALL patients had a significantly more favorable outcome than favorable outcome than B-cell lineage ALL patients only in the chemotherapy arm. A useful measure in risk assessment could be the rate of clearance of leukemic cells from the blood or bone marrow during the early phase of therapy. Slow clearance of the cells has proved to be an indicator of poor prognosis, requiring intensification therapy [39]. Improved understanding of the molecular pathogenesis of ALL, as well as the development of innovative molecular monitoring techniques, is beginning to provide both new prognostic information and insights into future therapeutic strategies. The identification of new molecular markers of disease may also increase our ability to tailor treatment for specific risk groups in ALL. Both T cell receptor (TCR) and genotypic stratification have been shown to contribute to risk-adapted management of adult T-cell lineage ALL [40]. Detection of MRD is also beginning to provide important prognostic information that may affect postremission strategies. This was applied in the GRAALL-03 trial, in which treatment decisions were based on the detection and quantification of leukemia cells at different times during postremission treatment [41]. Ultimately, the goal of risk-stratification was to provide the rationale for successful subset-specific therapeutic strategies to improve outcome for all adults with ALL. 11.10 Treatment of Elderly Patients A number of clinical and laboratory characteristics influence the response to treatment and thus the survival of patients with ALL. Among them, age is one of the most important prognostic variables [7]. Only few reports have been published on ALL in the elderly, but all confirmed the poor prognosis in elderly patients with ALL with survival rates of less than 10% at 5 years [42]. This may be related to the biology of leukemia in the elderly [7, 43] and/or could be related to an increase in the number of early deaths during induction [44, 45]. Toxicity is probably not mainly hematologic since regeneration after chemotherapy is not significantly delayed, but mainly extrahematologic. This may lead to incomplete application of a proposed treatment schedule, which additionally worsens the outcome. Another major reason for the poor outcome in elderly ALL patients is a higher prevalence of disease refractory to standard chemotherapy programs related to the higher incidence of adverse risk factors, particularly the increasing frequency of Philadelphia chromosome-positive ALL with age. The LALA group has developed special schedules for elderly patients with ALL since 1992. The LALA group initiated a study (LALAG-92) aimed at improving the prognosis of ALL in older patients [46]. Induction therapy was derived from the young adult protocol LALA-87 [15] with chemotherapy administered at lower dose and tailored according to the response assessed on day 15. In addition, the feasibility of maintenance with interferon (IFN) combined with chemotherapy was assessed (Fig. 11.6). The introduction of IFN in the treatment of ALL was supported by anecdotal reports suggesting that IFN may prove effective in some relapsing ALL [47, 48]. Moreover, in patients receiving IFN after bone marrow transplantation, the risk for subsequent relapse was reduced [49], and a hemizygous or homozygous deletion of the IFN gene has been reported in 30% of ALL patients, which led to the hypothesis that a functional or
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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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Page 93 and 94: Diagnosis of Acute Lymphoblastic Le
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Page 143 and 144: ALL Therapy: Review of the MD Ander
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Page 159 and 160: Philadelphia Chromosome-Positive Ac
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204 Chapter 16 · Treatment of Lymp
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216 Chapter 17 · The Role of Allog
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230 Chapter 18 · The Role of Autol
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238 Chapter 19 · Novel Therapies i
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248 Chapter 20 · Minimal Residual
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264 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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