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a 16.10 · Summary and Future Prospects 211 In this study, however, the overall CR rate of 56% and the DFS for chemotherapy were suboptimal [50]. It is a well-known fact that results of chemotherapy and SCT cannot be easily compared since retrospectively analyzed SCT patients generally represent a selected patient cohort excluding patients not achieving CR, with early relapse or poor general condition. Particularly patients with LBL generally achieve remission rapidly and if they relapse, they do it early. Thus it can be assumed that these patients are not represented in the transplantation cohort and that a significant number of the transplanted patients are already cured by previous chemotherapy. A recent study tried to circumvent these issues by an intent-to-treat analysis. In 34 T-LBL patients, SCT was planned upfront after an NHL/ALL-type induction regimen. SCT was actually realized in 29 patients (24 auto, 4 allo), which is a high proportion. The overall survival was 72% for all patients and 79% for those who actually proceeded to SCT. For auto SCT the DFS is 69% [34]. This is the first study showing convincingly that auto SCT may yield similar results as chemotherapy in an intent-to-treat analysis. 16.8.5 Summary Auto or allo SCT may confer an advantage in survival for high-risk LBL. However, in recent studies survival after chemotherapy is similar to the reported results of allo or auto SCT; furthermore, no convincing risk model for LBL is available at present and therefore clear indications for SCT in first CR are missing. Particularly for allo SCT results are still scarce and treatment-related morbidity and mortality is high; it should therefore probably be restricted to relapse patients. 16.9 Outcome of Salvage Therapy The outcome of patients with relapsed LBL was poor in most studies. The disease generally shows a rapid progression and response rates after salvage chemotherapy are low. Results of auto SCT are also inferior beyond first CR (Table 16.4). In a report from the EBMTR, the DFS for auto SCT in CR2 or in resistant disease was 31 and 15%, respectively, compared to 63% in CR1 [48]. Also in another large cohort, the DFS after auto SCT in CR1 was 76% compared to 38% for CR2 [49]. From single studies DFS rates between 14 and 50% have been reported for auto SCT in CR2 [14, 46, 55]. For allo SCT beyond first CR the DFS was low (16%), which seems to be a realistic result. The major problem is to achieve a stable second remission. Several new treatment options may be evaluated. Salvage treatment should aim to refer the patients to an allo SCT as soon as possible. In patients without a compatible donor auto SCT in second remission is an option if stem cells are available or may be performed as interim therapy before allo SCT. Therefore storage of peripheral stem cells during front-line treatment appears to be reasonable since particularly in patients without a sibling donor, the search for an unrelated donor may be too time-consuming. 16.10 Summary and Future Prospects For the development of future treatment strategies in adult LBL various questions remain open since no randomized studies are available. The use of ALL-type regimens appears to be justified although a prospective comparison with intensive NHL regimens is desirable. In this rare disease this aim could, however, only be achieved with large cooperative studies. The requirement for intensive prophylaxis of CNS relapse in T-LBL is evident. It remains, however, open whether this aim can be achieved by intensive intrathecal therapy and systemic high dose chemotherapy, whether CNS irradiation is required or whether it may be restricted to patients with stage III/IV disease. The major problem of local disease control is the effective treatment of mediastinal tumors. This may be achieved by increased dose for mediastinal irradiation, although this approach may compromise further chemotherapy due to bone marrow suppression. At the same time intensification of systemic treatment can be attempted since treatment-related mortality is generally low in LBL. The value of cytostatic drugs with particular effectivity in T-ALL should be analyzed. From adult T-ALL it is known that CYCLO and ARAC contributed to an improvement of overall results [29]. In childhood T-ALL intensive use of asparaginase [56] and MTX [57] contributed to better outcome. In T- LBL superior results were attributed to intensive treatment including cyclophosphamide, MTX, and dexamethasone during early phase of treatment. As a result no relapses occurred later than 1 year compared to
212 Chapter 16 · Treatment of Lymphoblastic Lymphoma in Adults other studies with relapses up to 5 years [7]. Also pretreatment with CYCLO pulses may play a role in T- LBL. In T-ALL the introduction of pretreatment with fractionated CYCLO in one study lead to a reduction of failure rate from 5/39 without CYCLO pretreatment to 0/8 with pretreatment [58]. The efficacy of fractionated CYCLO is also underlined by the successful hyper-CVAD regimen [18]. New cytostatic drugs such as 2-CDA, forodesine Hydrochloride, and nelarabine with specific activity on Tcells or immunotherapy with T-cell specific antibodies such as anti-CD3 and anti-CD52 (Campath) deserve evaluation in relapsed and refractory patients. For nelarabine it was shown recently that it is equally effective in relapsed T-ALL and T-LBL with response rates of 42 and 38%, respectively [59]. This drug is of interest not only for salvage therapy but also for integration in front-line therapy of T-LBL SCT may have a role in the treatment of high-risk patients with T-LBL although it is still not clear how high-risk patients have to be defined in the context of contemporary intensive ALL-type regimens. Particularly before auto SCT, intensive chemotherapy aiming to a high CR rate and effective tumor reduction seems to be necessary. New prognostic factors are required to define indications for SCT in first remission. The better characterization of biologic markers, e.g., immunophenotype of T-LBL, may contribute to this aim. Methods for MRD evaluation from bone marrow or even peripheral blood have to be established. Microarray analyses may contribute to characterization of disease biology and identification of new prognostic markers. It was already demonstrated that the majority of T-LBL patients show individual T-cell receptor rearrangements similarly to T-ALL. Thus, in the future, indications for SCT may be based at least partly on the evaluation of MRD. References 1. The Non-Hodgkin’s Lymphoma Classification Project (1997) A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 89:3909–3918 2. Groves FD, Linet MS, Travis LB, Devesa SS (2000) Cancer surveillance series: Non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 92:1240–1251 3. Harris NL, Jaffe ES, Diebold J, et al. (2000) The World Health Organization classification of neoplastic diseases of the haematopoietic and lymphoid tissues: Report of the Clinical Advisory Commit- tee Meeting, Airlie House, Virginia, November 1997. Histopathology 36:69–86 4. Raetz EA, Perkins SL, Bhojwani D, et al. (2006) Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Pediatr Blood Cancer 47:130–140 5. Foon KA, Herzog P, Billing RJ, Terasaki PI, Feig SA (1981) Immunologic classification of childhood acute lymphocytic leukemia. Cancer 47:280–284 6. Jaffe ES, Berard CW (1978) Lymphoblastic lymphoma, a term rekindled with new precision. Ann Intern Med 89:415–417 7. Reiter A, Schrappe M, Ludwig WD, et al. (2000) Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: A BFM group report. Blood 95:416–421 8. Gökbuget N, Hoelzer D (2006) Treatment of adult acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program, pp 133–141 9. Engelhard M, Brittinger G, Gerhartz HH, Kuse R, Steinke B (1996) Lymphoblastic lymphoma: Results of a prospective treatment trial (BMFT study). Br J Haematol 93:1391a 10. Soslow RA, Baergen RN, Warnke RA (1999) B-lineage lymphoblastic lymphoma is a clinicopathologic entity distinct from other histologically similar aggressive lymphomas with blastic morphology. Cancer 85:2648–2654 11. Hoelzer D, Gökbuget N, Digel W, et al. (2002) Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 99:4379– 4385 12. Bernasconi C, Brusamolino E, Lazzarino M, et al. (1990) Lymphoblastic lymphoma in adult patients: Clinicopathological features and response to intensive multiagent chemotherapy analogous to that used in acute lymphoblastic leukemia. Ann Oncol 1:141–146 13. Santini G, Congiu AM, Coser P, et al. (1991) Autologous bone marrow transplantation for adult advanced stage lymphoblastic lymphoma in first CR. A study of the NHLCSG. Leukemia 5(Suppl)1: 42–45 14. Morel P, Lepage E, Brice P, et al. (1992) Prognosis and treatment of lymphoblastic lymphoma in adults: A report on 80 patients. J Clin Oncol 10:1078–1085 15. Zinzani PL, Bendandi M, Visani G, et al. (1996) Adult lymphoblastic lymphoma: Clinical features and prognostic factors in 53 patients. Leuk Lymphoma 23:577–582 16. Bouabdallah R, Xerri L, Bardou VJ, et al. (1998) Role of induction chemotherapy and bone marrow transplantation in adult lymphoblastic lymphoma: A report on 62 patients from a single center. Ann Oncol 9:619–625 17. Sweetenham JW, Pearce R, Taghipour G, et al. (1997) Adult Burkitt’s and Burkitt-like non-Hodgkin’s lymphoma7Outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: Results from the European Group for Blood and Marrow Transplantation. J Clin Oncol 14:2465–2472 18. Thomas DA, O’Brien S, Cortes J, et al. (2004) Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood 104:1624–1630
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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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262 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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