Acute Leukemias - Republican Scientific Medical Library

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a 16.6 · Mediastinal Tumors 207 Center, CR rates of 80% and DFS of 45% could be achieved with different ALL-type regimens (L2, L10, L17) [30]. Similar or even better results with CR rates between 55 and 100% and DFS rates between 45 and 67% were reported later for ALL-type regimens [9, 11, 12, 14–16, 31, 32]. 16.4.2.1 MDACC The MD Anderson Cancer Center (MDACC) reported the results of 33 patients treated according to the Hyper-CVAD regimen. The schedule is based on alternating cycles with fractionated cyclophosphamide (CY- CLO) combined with other drugs and cycles with HD- ARAC and methotrexate (HD-MTX). The majority of patients received consolidative mediastinal irradiation after eight cycles. The cohort included mainly T-LBL (80%) with 70% stage III-IV disease. The CR rate was 91% with 9% partial responses. The progression-free survival at 3 years was 66% and the survival 70% with 62% and 67% for the T-cell subtype, respectively. The major relapse localization was the mediastinum (50% of the relapses). Ten percent of the CR patients developed CNS involvement at relapse. Except CNS involvement at diagnosis, no prognostic factors could be identified [18]. 16.4.2.2 GMALL The largest cohort of T-LBL was reported by the German Multicenter Study Group for Adult ALL (GMALL). Forty-five patients were treated with standard 8-drug induction including prophylactic CNS irradiation and mediastinal irradiation followed by consolidation and reinduction therapy. In the majority of patients, treatment ended after reinduction at about 30 weeks. The CR rate was 93%. Thirty-six percent of the patients relapsed. No late relapses after the first year from diagnosis were observed. The majority of relapses (47%) involved the mediastinum, although six out of seven patients had received mediastinal irradiation with 24 Gy. The survival was 51% at 7 years, 65% for CR patients, and the DFS was 62%. Advanced stage, age, LDH and other parameters had no prognostic impact [11]. 16.4.3 Summary These studies provide strong evidence that intensive chemotherapy in T-LBL may lead to favourable outcome without SCT in first CR even in patients with advanced disease and that particularly late relapses may be avoided to a large extent. Additional evidence for the high effectivity of ALL-type chemotherapy in T-LBL comes from a report on 105 children with T-LBL. The event-free survival of 90% was superior to previous studies in childhood T-LBL [7]. 16.5 CNS Prophylaxis Initial CNS involvement is observed in approximately 7% of LBL patients, which is similar to the incidence in ALL [11, 12, 14, 18, 19, 30, 35]. As in ALL, a high rate of CNS relapse (32–50%) was observed in earlier studies where patients did not receive specific CNS-directed prophylaxis [19, 35]. The inclusion of i.th. therapy leads to a substantial reduction of the CNS relapse rate [19] which ranged from 0% to 36% in studies with CNS prophylaxis based on i.th. therapy only [12, 19, 23, 30, 35] and from 3% to 21% in studies with i.th. therapy and CNS irradiation [12, 23, 26, 35]. Several historical comparisons underline the potential role of prophylactic CNS irradiation [23, 36]. In the GMALL study, 91% of the study patients received CNS irradiation and all of them had intensive i.th. therapy. This approach proved to be effective since only one of 42 CR patients experienced a CNS relapse [11]. CNS irradiation is not part of the Hyper-CVAD regimen, which, however, included i.th. therapy and systemic high-dose therapy. CNS involvement at relapse was seen in three of 30 CR patients [18]. Overall published results underline the importance of effective CNS prophylaxis in LBL and there is some evidence that CNS irradiation is a successful approach. It may be reasoned, however, whether CNS irradiation could be omitted in patients with stage I-II disease in order to avoid toxicity and treatment delays during induction therapy. 16.6 Mediastinal Tumors One major specific issue in T-LBL is the role of mediastinal tumors (MedTu) as a cause for initial treatment failure and as relapse localization. Most patients show large MedTu at diagnosis, which in some patients even leads to emergency situations with acute respiratory distress and/or acute vena cava superior syndrome.
208 Chapter 16 · Treatment of Lymphoblastic Lymphoma in Adults After induction, residual MedTu are sometimes difficult to assess and hamper the confirmation of CR. The mediastinum is also the most frequent site of recurrence. Several questions arise from this issue, such as prognostic impact of residual tumors, useful diagnostic procedures, and additional directed treatment of MedTu, which may either be prophylactic or therapeutic. 16.6.1 Prognostic Impact of Residual Mediastinal Tumors The rapid achievement of CR had a prognostic impact in childhood LBL. Three out of 64 T-LBL patients with complete response at day 33 of induction showed local progress (5%) compared to three out of 35 (9%) with only partial remission [7]. In this study, however, the overall incidence of local progression was very low. One pediatric study demonstrated an inferior survival in patients without normalization of chest radiography after induction [37]. Also in adult T-LBL an inferior outcome was observed in patients with incomplete response to induction therapy, which was mainly due to residual MedTu [11]. On the other hand, in patients treated with a HD-MTX based regimen none of three patients with residual mass after induction relapsed [28]. 16.6.2 Diagnostic Procedures Not surprisingly, in T-LBL patients with large MedTu often residual structures are detectable after induction therapy by X-ray or computed tomography (CT). Additional diagnostic procedures aim to answer the question whether this is necrotic or scar tissue or whether vital tumor cells are present. When resection or biopsy was performed in 10 pediatric T-LBL patients with residual tumor after induction therapy, necrotic tissue was found in all cases [7]. Imaging techniques such as positron emission tomography (PET) are probably not helpful very early after induction therapy due to the ongoing effects of the chemotherapy. They are, however, important for staging at later time-points. Recently it was reported that persistently positive PET results were highly predictive for residual or recurrent disease in NHL [38]. In the GMALL studies PET diagnostics are performed in patients with residual mediastinal structures after induction and first consolidation. Altogether there is some evidence that residual Med- Tu after induction therapy are associated with increased relapse risk. In addition to the intensification of systemic chemotherapy, the most frequently discussed approach for prevention of mediastinal recurrence and treatment of residual tumors is mediastinal irradiation (MedRad) with two principally different strategies: irradiation of all patients with MedTu or irradiation in patients with residual tumor only. 16.6.3 Mediastinal Irradiation Mott et al. reported a significant advantage in terms of DFS for pediatric T-LBL patients with low-dose irradiation (15 Gy) (66%) compared to 18% for those without in an early study with probably suboptimal chemotherapy [39]. Other strategies in childhood T- LBL included MedRad in case of emergency only [7, 40, 41]. In the latter study the local recurrence rate (7%) was very low although no MedRad was administered. This may be due to a more rigorous early application of cyclophosphamide and ARAC and HD MTX, specifically designed as “extra compartment protocol” during consolidation [7]. This is underlined by the results of an HDMTX-based NHL protocol in adult T- LBL where only three of 14 relapses occurred in the mediastinum [28]. In the GMALL series of adult T-LBL, the mediastinal relapse rate was higher (47% of all relapses), despite an induction therapy similar to the pediatric approach and prophylactic MedRad with 24 Gy in 85% of the patients early during or after induction chemotherapy. Consolidation with HD-MTX was, however, less intensive. Mediastinal relapses occurred in patients with complete resolution of MedTu as well as in those with residual tumors after induction therapy [11]. In the cohort of the MDACC, the majority (74%) of patients had received MedRad with 30–39 Gy after eight cycles of chemotherapy. Three patients progressed before this time-point and one out of three patients without MedRad due to other reasons experienced mediastinal relapse. The mediastinal relapse rate was 12% in those who had received MedRad [18]. Altogether these findings underline that effective treatment of MedTu is an important specific issue in the treatment of adult T-LBL. In pediatric LBL low mediastinal recurrence rates are achieved by intensive chemotherapy, which may, however, not be feasible in adult
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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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258 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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