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284 Chapter 23 · Emergencies in <strong>Acute</strong> Lymphoblastic Leukemia preinduction therapy with glucocorticoids, adding vincristine and cyclophosphamide in cases of B-cell ALL, is a preferred means for the amelioration of hyperleukocytosis [46, 47]. Preinduction chemotherapy in combination with urate oxidase has dramatically decreased the frequency of tumor lysis syndrome and the need for hemodialysis in patients with B-ALL [48]. If administration of chemotherapy is not feasible in a patient with hyperleukocytosis and symptoms of leukostasis, or it must be delayed secondary to the significant metabolic abnormalities, renal insufficiency, or possibly pregnancy, emergency leukapheresis may be used to decrease or stabilize WBC count. However, based on the available data, leukapheresis cannot be recommended as a routine therapy or as a form of tumor debulking in an asymptomatic adult patient with ALL. 23.6 SVC/Mediastinal Mass Patients with ALL (particularly T-ALL) may present with symptoms of cough, dyspnea, stridor, or dysphagia from the tracheal and esophageal compression by a mediastinal mass. More than 27% of children who presented with mediastinal mass have acute airway compromise [49]. Compression of great vessels by a bulky mediastinal mass may also lead to the life-threatening superior vena cava syndrome. In addition to the above-mentioned symptoms, patients might develop cyanosis, facial edema, increased intracranial pressure, and syncope. The prognosis of patients with SVC syndrome is strongly correlated with the prognosis of underlying disease. Diagnosis of primary condition must be established promptly, and therapy with steroids, radiation, and/or chemotherapy must be initiated without delay. When the therapeutic goal is only palliation of SVC syndrome, or if emergent treatment of the venous obstruction is required, direct opening of the occlusion with endovascular stenting and angioplasty with possible thrombolysis should provide prompt relief of symptoms [50]. Other medical measures such as head elevation and oxygen administration, which can reduce cardiac output and venous pressure, might be helpful. 23.7 DIC Disseminated intravascular coagulation (DIC) is a known complication of ALL in children [51–53] and adults [54]. The frequency of DIC in adults is reported to be 10–16% at presentation and 36–78% during remission induction therapy [55–57]. Hypofibrinogenemia (< 100 mg/dl) was detected in 41% of patients with ALL at the time of diagnosis and after initiation of therapy [58]. Hemorrhagic symptoms are usually mild; however, serious hemorrhage occurs in 20% of patients with laboratory evidence of DIC [55]. Patients who develop DIC tend to have a higher WBC (77900/mm 3 vs. 9400/mm 3 ) counts and a higher frequency of palpable splenomegaly than the patients who do not develop DIC. However, no statistically significant relationship was established between DIC and age, FAB subtype, immunophenotype, karyotype, LDH, and percentage of blasts in the bone marrow. An etiologic link between CD34 expression and DIC has been suggested [57]. ALL patients who developed DIC after the initiation of chemotherapy had a lower platelet level and higher level of the E-fragment of serum fibrinogen/fibrin degradation products (FDP) at presentation, suggesting that they already had DIC at presentation. These findings indicate that perhaps patients with high WBC counts, higher FDP level, a low platelet count, and splenomegaly at presentation require closer monitoring for DIC after the initiation of chemotherapy. The best way to treat DIC is to treat the underlying ALL. However, exacerbation of DIC may occur during induction therapy and with ATLS. The coagulation profile must be obtained at the time of diagnosis and repeated frequently, especially when laboratory evidence of DIC is detected, to guide the replacement therapy in DIC. Theoretical concerns for exacerbating DIC with blood products have not been substantiated clinically, and hemostatic competence to avoid severe bleeding must be maintained. It is reasonable to keep activated partial thromboplastin time (aPTT) at about 1.5 times normal level with FFP, platelets at about 50000/ll with platelet transfusions, and fibrinogen level over 100 mg/dl with cryoprecipitate. Heparin therapy is rarely indicated in the patient with ALL and DIC. However, if required, heparin levels should be followed, since the monitoring aPTT may lead to over- or under-treatment of the patient.
a 23.9 · Neurological Complications 285 23.8 L-Asparaginase and Coagulopathy L-asparaginase (L-asp), an enzyme from bacteria that destroys the amino acid asparagine, required primarily by leukemic cells, is an important component of combination chemotherapy for ALL. L-asp can produce depletion of many of the hemostatic, anticoagulant, and fibrinolytic factors such as fibrinogen, factors IX, XI, antithrombin III, proteins C and S, and plasminogen with an associated risk of thrombosis and hemorrhage [59– 61]. These effects are likely due to the decreased protein synthesis by the liver, rather than clotting factor consumption or the production of the abnormal molecules [60, 62, 63]. This reduction of the synthesis of the clotting factors appears to be proportional to the elimination of asparagine from the plasma, and normalizes as soon as L-asp is discontinued [64]. Although marked reductions in fibrinogen and factors IX and XI due to L-asp occurs frequently, excessive bleeding is rare [60]. There is no prospective data to suggest a fibrinogen level at which replacement is required. It is reasonable to temporarily discontinue the L-asp when fibrinogen level decreases to 50–70 mg/dl. However, in general, we do not recommend fibrinogen replacement therapy in an asymptomatic patient regardless of fibrinogen level. When clinically significant bleeding occurs or a patient is required to undergo a surgical procedure, therapy with cryoprecipitate or FFP is usually successful in correcting the hemostatic defect [65]. The concentration of the anticoagulant proteins AT III, protein C, and protein S can decrease to 30% of normal level in patients treated with L-asp, levels low enough to predispose to thrombosis. The low level of circulating fibrinogen does not appear to offset the risk of thrombosis, since cases of severe central nervous system (CNS) thrombosis are reported in patients with a fibrinogen level of 29 mg/dl [66]. Prophylactic use of FFP was ineffective in preventing the decrease in antithrombin III level induced by L-asp [67]. In a setting of L-asp therapy, the presence of an inherited hypercoagulable state such as Factor V Leiden, or the prothrombine gene mutation was shown to increase the risk of thrombosis in some studies [68], but not in others [69]. The presence of the antiphospholipid antibody increases the risk of thrombosis in patients treated with L-asp [69]. CNS thrombosis occurs in approximately 4% of adult patients with ALL, usually 2–3 weeks after the initiation of therapy with L-asp. Although most patients recover without significant neurological consequences, death and permanent neurological defects have been reported [70–72]. While the risk of thrombosis is greatest during the remission induction phase of chemotherapy with L-asp, it may occur at any stage of therapy [73]. Pegaspargase, a modified form of native E. coli asparaginase, has been reported to cause hypofibrinogenemia in more than 50% of patients, however the clinical evidence of thrombosis were rarely encountered [73a, 73b]. Pancreatitis was reported in approximately 15% of patients treated with E. coli L-asparaginase and in 1–4% of patients receiving pegaspargase [73c]. Hepatotoxicity and hyperbilirubinemia are common complications of asparaginase therapy, although typically are grades 1–2 and are reversible with the discontinuation of therapy [73b]. However, in one study grade 4 hyperbilirubinemia was reported in 54% of patients who received 1–4 doses of pegasparaginase [73a]. The rate of allergic reaction appears to be less frequent in patients receiving pegasparaginase compared to ones treated with E. coli L-asparaginase [73d]. 23.9 Neurological Complications Five to ten percent of adult patients with ALL may present with clinically significant neurological findings related to the leukemic infiltration of CNS [74]. CNS involvement may manifest as generalized headache and papilledema from raised intracranial pressure, blindness due to the bilateral optic nerve infiltration, trigeminal neuralgia secondary to 7th cranial nerve infiltration and lymphomatous meningitis, transverse myelopathy, and epidural spinal cord compression [75–78]. Significance of such symptoms must be recognized immediately and chemotherapy with systemic and intrathecal methotrexate or cytarabine, steroids, and radiation therapy should be administered promptly in hopes to prevent permanent damage. In a study of 36 patients with leukemic involvement of the nervous system (46 episodes of CNS involvement) 21.7% of the episodes involved the cranial nerve, most commonly the bulbar motor, facial, and optic nerves [79]. Although CNS involvement is likely to require radiation therapy, the optimal protocol for radiation administration is yet to be determined. Patients with symptomatic cranial nerve palsy are recommended to
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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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a 14.2 · Molecular Biology of the
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a 14.3 · Treatment of Ph+ ALL 181
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a 14.4 · Hematopoietic Stem Cell T
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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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