Acute Leukemias - Republican Scientific Medical Library

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a 17.6 · Long-Term Complications of Allogeneic SCT 225 Table 17.5. Risk of relapse following non-T-cell depleted allogeneic transplantation in ALL Study No. patients Risk of relapse (%) Doney, 1991 [20] 192 (SCT in CR2) No GVHD 80 Grade II-IV GVHD 40 Sullivan, 1989 [72] 200 (SCT in CR) No GVHD 56 Acute GVHD 27 Acute & chronic GVHD 22 (SCT in relapse) No GVHD 81 Acute GVHD 39 Acute & chronic GVHD 43 Horowitz, 1990 [73] 349 (SCT in CR1) No GVHD 44 (IBMTR) Acute GVHD 17 Chronic GVHD 20 Acute & chronic GVHD 15 Direct and indirect evidence suggests that donor T cells and NK cells are primary mediators of GVM. The target antigens for the GVM response are unknown. It is difficult to generate a T-cell response to lymphoblasts. ALL cells do not express costimulatory molecules and are poor stimulators of T-cell reactivity. G-CSF mobilized PBSC have also been investigated as a source of donor lymphocytes for adoptive therapy. The numbers of T cells and NK cells found in PBSC are comparable to those present in a DLI. Eleven patients (four CML, five AML, one ALL) received PBSC postrelapse; all patients with acute leukemia received cytoreductive therapy prior to PBSC. All six patients with acute leukemia achieved a CR, with median remission duration of 24 weeks [77]. Perhaps the success noted in this study resulted, in part, from the cytoreduction prior to DLI, which may play an important role in the DLI efficacy. DLI has been combined with IL-2 in an attempt to augment efficacy in ALL patients. Four patients with relapsed ALL were treated with this approach and all responded [77]. No conclusions can be drawn from such small series of patients. However, these results are intriguing, and suggest that adoptive cell therapy and associated immunomodulatory therapy may be further developed as a treatment modality, and may eventually become a viable salvage option for ALL relapses following allogeneic transplants. 17.6 Long-Term Complications of Allogeneic SCT Socie et al. analyzed the characteristics of 6691 patients listed in the IBMTR who underwent allogeneic SCT for AML, ALL, CML, or aplastic anemia between January 1980 and December 1993 [78]. The median duration of follow-up was 80 months. Mortality rates in this cohort were compared with those of an age-, sex-, and nationality-matched general population. All patients were free of disease 2 years posttransplant, with 89% survival at 5 years. Mortality rates remained significantly higher than the general population throughout the study among patients who underwent transplantation for ALL or CML, and through the ninth year for patients who had AML. Specifically, for patients with ALL, the relative mortality rate was 20.1 2 years after transplantation, 25.9 5 years after transplantation, and 15.4 10 years after transplantation. Not surprisingly, recurrent leukemia was the chief cause of death for patients who underwent SCT for leukemia and GVHD among those in either disease category, followed by infection, new cancer, and organ failure. Older age was associated with an increased risk of relapse in the ALL group, with 48% relapse observed in ALL compared with 11% relapses in the overall group. Chronic GVHD was the second leading cause of death overall, with 23% observed in the ALL cohort. A low incidence of secondary cancer was reported overall (6%), with a slightly higher rate observed
226 Chapter 17 · The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult Acute Lymphoblastic Leukemia (ALL) in the ALL group (10%). Increased rates of secondary cancer may be noted with longer follow-up. Quality of life and psychosocial functioning are major issues following allogeneic SCT. Broers et al. evaluated quality of life in a prospective study of 125 consecutive patients who underwent BMT between 1987 and 1992 [79]. Patients were evaluated with questionnaires measuring quality of life, functional limitations, psychological distress, anxiety, depression, and self-esteem. Questionnaires were answered prior to the BMT, 1 month after following discharge, at 6 months, 1 year, and 3 years after BMT. Nearly 90% of patients reported a good to excellent quality of life at 3 years. Changes in quality of life and psychological distress could be explained entirely by changes in functional limitations and somatic symptoms. The minority of patients who reported a worse quality of life reported experiencing continued serious functional limitations. One such limitation is the late neurotoxic effects of BMT on cognitive functioning. Harder et al. investigated this phenomenon in a consecutively treated cohort of long-term adult survivors [80]. Forty patients were included, 87.5% had undergone allogeneic transplantation. All received total body irradiation up to 12 Gy. Assessment took place 22–82 months after BMT. Mild to moderate cognitive impairment was found in 24 patients (60%). Compared with healthy population norms, selective attention and executive function, information processing speed, verbal learning, and verbal and visual memory were most likely to be affected. Therefore, cognitive functioning should be used as an outcome parameter in BMT studies, and emphasis should be placed on interventions that help patients cope with their physical limitations. 17.7 Conclusion In conclusion, allogeneic SCT has been demonstrated to have a major therapeutic benefit for selected patients with high-risk ALL. However, much work remains to be done to improve survival for patients with this challenging disease. Results of trials of novel strategies are eagerly awaited including the incorporation of molecularly targeted chemotherapy, targeted immunotherapy using monoclonal antibodies or adoptive cellular therapy, and novel nonmyeloablative preparative regimens with promise to decrease treatment-related morbidity and improve survival. References 1. Kantarjian HM, et al. (2000) Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 18(3):547–561 2. Linker C, et al. (2002) Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 20(10):2464–2471 3. Larson RA (2000) Recent clinical trials in acute lymphocytic leukemia by the Cancer and Leukemia Group B. Hematol Oncol Clin North Am 14(6):1367–1379 4. Hoelzer D, et al. (1988) Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71(1):123–131 5. Charrin C, Mugneret F (1996) Cytogenetics of recurrent acute leukemia. Rev Prat 46(1):37–41 6. Faderl S, et al. (1998) Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 91(11): 3995–4019 7. Wetzler M, et al. (1999) Prospective karyotype analysis in adult acute lymphoblastic leukemia: The cancer and leukemia Group B experience. Blood 93(11):3983–3993 8. Wetzler M (2000) Cytogenetics in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am 14(6):1237–1249 9. Stock W, Estrov Z (2000) Studies of minimal residual disease in acute lymphocytic leukemia. Hematol Oncol Clin North Am 14(6):1289–1305, viii–ix 10. Hoelzer D (2002) Acute lymphoblastic leukemia. American Society of Hematology, Pennsylvania 11. Brisco J, et al. (1996) Relationship between minimal residual disease and outcome in adult acute lymphoblastic leukemia. Blood 87(12):5251–5256 12. Radich JP, et al. (1995) Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: Results and implications in 346 patients. Blood 85(9):2632–2638 13. Gehly GB, et al. (1991) Chimeric BCR-abl messenger RNA as a marker for minimal residual disease in patients transplanted for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 78(2):458–465 14. Mitterbauer G, et al. (1999) Quantification of minimal residual disease in patients with BCR-ABL-positive acute lymphoblastic leukaemia using quantitative competitive polymerase chain reaction. Br J Haematol 106(3):634–643 15. Miyamura K, et al. (1992) Detection of Philadelphia chromosomepositive acute lymphoblastic leukemia by polymerase chain reaction: Possible eradication of minimal residual disease by marrow transplantation. Blood 79(5):1366–1370 16. Preudhomme C, et al. (1997) Good correlation between RT-PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL). Leukemia 11(2):294–298 17. Blaise D, et al. (1990) Allogeneic or autologous bone marrow transplantation for acute lymphoblastic leukemia in first complete remission. Bone Marrow Transplant 5(1):7–12 18. Chao NJ, et al. (1991) Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia during first complete remission. Blood 78(8):1923–1927
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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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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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