Acute Leukemias - Republican Scientific Medical Library

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132 Chapter 9 · General Approach to the Therapy of Adult <strong>Acute</strong> Lymphoblastic Leukemia include addition of known chemotherapy drugs or further intensification of chemotherapy doses, but also incorporation of new and targeted drugs (e.g., monoclonal antibodies and tyrosine kinase inhibitors), reassessment of the position of stem cell transplant as part of consolidation in first remission, use of molecular monitoring for minimal residual disease, and hence establishment of novel prognostic systems leading to more patient-specific therapy approaches based on risk profile and ALL subset (Table 9.1). The backbone of induction therapy consists of vincristine, steroids, and anthracyclines to which various other drugs such as L-asparaginase, cyclophosphamide, or cytarabine have been added. Dexamethasone has replaced prednisone for better antileukemia activity and achievement of higher levels in the CSF [5, 6]. Retrospective studies suggested that early dose intensification of daunorubicin would lead to superior leukemia-free survival and cure rates. Italian investigators used three cycles of daunorubicin at 30 mg/m2/day for 3 days for a total of 270 mg/m2 during induction [7]. They reported long-term disease-free survival (DFS) of 55%. Other studies have not confirmed an improvement in DFS, but noted fewer relapses after 2 years [8]. Highdose cytarabine and mitoxantrone or even single-agent high-dose idarubicin without the traditional vincristine-steroid combination as the basic therapy have been investigated, but there is little evidence of their advantage [9, 10]. Overall, it has been difficult to prove higher remission rates with these strategies. However, intensified induction may result in better quality responses and longer survival in subsets of patients. Maximum supportive care is a significant contributor to the success of induction therapy. Use of antibiotics including antifungal prophylaxis, laminar air flow rooms for older patients (³60 years), and hematopoietic growth factors permit administration of dose-intensive therapy with relatively low induction mortality due to myelosuppression-associated complications. The Cancer and Leukemia Group B (CALGB) randomized untreated ALL patients to receive either G-CSF or placebo during intensive remission induction therapy [11]. Patients who received G-CSF experienced a shorter time to recover the neutrophil count ³1´109/L (16 days vs. 22 days, p
a 9.3 · New Agents 133 dose methotrexate may be especially effective in lowrisk B-lineage ALL and T-ALL, whereas cyclophosphamide and L-asparaginase have led to improved outcome in T-lineage ALL patients [12, 13]. Early use of stem cell transplantation (SCT) remains disputed. Although recommended for patients with poor-prognosis ALL (Philadelphia-chromosome-positive, 11q23 translocations), the benefit of SCT for standard-risk patients in first CR is not established [14]. The Eastern Cooperative Oncology Group (ECOG) together with the <strong>Medical</strong> Research Council of the United Kingdom (MRC UK) is investigating early matched-related allogeneic SCT for those CR patients < 50 years who have a histocompatible donor, whereas all other patients are randomized between autologous SCT and consolidation therapy followed by maintenance for 2.5 years [15]. In the standardrisk group, the 5-year EFS rates were 66% with allogeneic SCT and 45% for the randomized group (p = 0.06) whereas the rates were 44% and 26% for high-risk patients. These data require further maturation, but may suggest that allogeneic SCT in first CR for patients < 50 years may be beneficial not only for high-risk patients. The backbone of maintenance therapy has remained fairly constant throughout the various ALL regimens and consists of vincristine, prednisone, 6-mercaptopurine, and methotrexate for the duration of 2–3 years. Although maintenance therapy is proven to be beneficial in ALL, there is so far no evidence that intensification of maintenance provides any additional benefit [16, 17]. No maintenance therapy is given to patients with Burkitt leukemia (mature B cell ALL) as these patients respond well to short-term, dose-intensive regimens and relapse after 1 year in remission is rare. Classic maintenance schedules have also not proven valuable in patients with Philadelphia chromosome-positive ALL although for the opposite reason. These patients may benefit from incorporation of tyrosine kinase inhibitors (e.g. imatinib) with or without additional chemotherapy. Improvements have been achieved in some ALL subsets such as mature B cell ALL and T lineage ALL (including lymphoblastic lymphoma/leukemia) where the prognosis has been traditionally poor. Incorporation of high doses of cytarabine and cyclophosphamide, as well as L-asparaginase in the consolidation of T lineage ALL have increased the cure rates up to 50–60% [18]. Similar cure rates are now achieved in patients with mature B cell ALL when treated with high doses of cytarabine and methotrexate and hyperfractionated cyclophosphamide administered in short-term, dose-intensive regimens [12, 13]. 9.3 New Agents Several novel agents are being investigated in ALL (Table 9.2). The two groups of agents that have the potential to make the biggest impact currently are the tyrosine kinase inhibitors and the monoclonal antibodies (rituximab, alemtuzumab, anti-B4bR). CD20 is expressed in around 35% of ALL patients with higher expression found in Philadelphia chromosome-positive ALL and mature B-cell ALL. In addition, it was found that presence of CD20 on ALL blasts is associated with worse outcome [19]. Thus, including rituximab as part of the induction/consolidation part of therapy may improve the prognosis of ALL patients further [20]. ALL blasts also show high expression of the CD52 antigen. Unlike CD20, CD52 is also expressed on cells of T lineage and use of the anti-CD 52 monoclonal antibody alemtu- Table 9.2. Investigational agents in ALL Class of agent Example Nucleoside analogs Clofarabine Nelarabine (Compound 506U) Purine nucleoside BCX1777 phosphorylase inhibitors Liposomal compounds Tyrosine kinase inhibitors Liposomal vincristine Liposomal daunorubicin Imatinib, dasatinib, nilotinib Antiangiogenesis agents Oligonucleotides BCL-2 antisense Monoclonal Rituximab (anti-CD20) antibodies Alemtuzumab (anti-CD52) Anti-B4bR (anti-CD19 + ricin) Gemtuzumab (anti-CD33) Anti-CD7 + ricin Flavones Flavopiridol Proteasome inhibitors Bortezomib Others Pegylated asparaginase, bryostatin, arsenic trioxide
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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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Page 79 and 80: Molecular Biology and Genetics Meir
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Page 93 and 94: Diagnosis of Acute Lymphoblastic Le
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Page 105 and 106: Acute Lymphoblastic Leukemia: Clini
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Page 143 and 144: ALL Therapy: Review of the MD Ander
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Page 149 and 150: Treatment of Adult ALL According to
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Page 159 and 160: Philadelphia Chromosome-Positive Ac
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a References 185 2. Kurzrock R, Sht
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a References 187 56. Mori T, Manabe
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a References 189 acute lymphoblasti
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192 Chapter 15 · Burkitt’s Acute
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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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