Acute Leukemias - Republican Scientific Medical Library

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The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult <strong>Acute</strong> Lymphoblastic Leukemia (ALL) Partow Kebriaei, Richard Champlin Contents 17.1 Introduction ................... 215 17.2 Prognostic Factors in Adult ALL .... 215 17.3 Results with Allogeneic Transplantation for High-Risk ALL ........... 216 17.3.1 First Complete Remission ...... 216 17.3.2 Beyond CR1 ............... 218 17.3.3 Primary Refractory ALL ....... 218 17.4 Philadelphia Chromosome-Positive ALL .......................... 218 17.5 Factors Influencing Transplant Outcome ..................... 220 17.5.1 Preparative Regimens ........ 220 17.5.1.1 Radiation-based ...... 220 17.5.1.2 Nonradiation-based .... 220 17.5.1.3 Nonmyeloablative SCT (NMSCT) ........... 221 17.5.2 Source of Stem Cells ......... 222 17.5.2.1 Bone Marrow vs. Peripheral Blood Stem Cells . . 222 17.5.2.2 Umbilical Cord Blood (UCB) .............. 222 17.5.3 Source of Donor Cells: Partially Matched Related or Matched Unrelated Donors ........... 223 17.5.4 The Role of T-Cell Depletion . . . 224 17.5.5 Immunomodulation with DLI . . . 224 17.6 Long-Term Complications of Allogeneic SCT ................. 225 17.7 Conclusion .................... 226 References ......................... 226 17.1 Introduction Adult patients with acute lymphoblastic leukemia (ALL) can now achieve complete remission (CR) rates of 80– 90% [1–3]. However, only 25–50% of these patients achieve long-term, disease-free survival. Current research efforts are focused on innovative postremission strategies with the goal of improving disease-free (DFS) and overall survival (OS). The identification of different prognostic groups based on the biology of the malignant clone and prognostic factors allows for risk-adapted therapy. Multiple randomized trials have demonstrated that hematopoietic stem cell transplantation (SCT) improves the outcome of patients with highrisk ALL. In this chapter, we will define the different disease risk groups, the clinical outcomes of major transplant trials for ALL, and the therapeutic factors that affect outcome after SCT. 17.2 Prognostic Factors in Adult ALL Several biologic features and specific clinical characteristics have been consistently noted to influence the outcome of adult ALL and impact on risk-stratification (Table 17.1). Older age, a high white blood cell count (WBC) at presentation, and failure to achieve a clinical remission within the first 4 weeks of treatment are generally accepted adverse clinical features. The detection of spe-
216 Chapter 17 · The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult <strong>Acute</strong> Lymphoblastic Leukemia (ALL) Table 17.1. Adverse prognostic features in Adult ALL Age greater than 60 years* WBC count greater than 30000/lL Cytogenetics: t(9;22)(q34;q11), trisomy 8, t(4;11)(q21;q23), monosomy 7, a hypodiploid karyotype, t(1;19)(q23;p13) Delayed time to complete remission, greater than 4 weeks * Established in US series; German series use age 30, 35, or 50 years as cut-off. cific recurring cytogenetic abnormalities has emerged as the most important prognostic factor for risk stratification of adults with ALL [4]. Clonal chromosomal aberrations can be detected in cells from 62% to 85% of adult ALL patients, and numerous studies have shown their significance as predictors of outcome [5, 6]. In one review of this literature, six abnormalities were associated with unfavorable outcome, defined as having a 0.25 or less probability of continuous CR at 5 years. These included, in decreasing frequency, t(9;22)(q34;q11), trisomy 8, t(4;11)(q21;q23), monosomy 7, a hypodiploid karyotype, and t(1;19)(q23;p13) [7, 8]. In addition to the adverse prognostic factors listed in Fig. 17.1, the detection of minimal residual disease (MRD) using qualitative or semiquantitative polymerase chain reaction (PCR) or flow cytometric techniques also provides important prognostic information [9]. MRD levels have been investigated both before and after transplantation, and this topic is addressed in a separate chapter of this book. In brief, persistent MRD positivity postinduction appears to be associated with an increased risk of relapse [10]. Brisco, et al. studied 27 adults with B-lineage ALL for MRD in first complete remission (CR1). Relapse occurred in eight of nine patients with a high level of disease detected using semiquantitative PCR (levels > 10 –3 ), compared to six of 13 patients with lower MRD levels (levels < 10 –3 ) [11]. MRD positivity after transplant has been most extensively studied in Philadelphia chromosome (Ph)positive ALL. In 28 patients evaluated, Radich, et al. found that the relative risk (RR) for relapse was significantly higher for patients with a detectable BCR/ABL transcript following transplantation than for those without detectable BCR/ABL (RR =5.7, p=0.025) [12]. The prognostic significance of the PCR assay remained after controlling for other prognostic variables. The risk of relapse was greater for patients with a p190 fusion transcript than for those with p210 BCR/ABL. The median time from detection of a positive PCR result to relapse was 94 days. Other investigators have found similar results [13–16]. Generally, patients who are persistently BCR/ABL negative following transplantation are unlikely to relapse. Conversely, patients who are BCR/ ABL+ following transplantation are at high risk for subsequent relapse. 17.3 Results with Allogeneic Transplantation for High-Risk ALL 17.3.1 First Complete Remission Review of a number of small, phase II trials in high-risk adult ALL who have undergone ASCT in CR1 suggests a higher DFS when compared with historic controls based on conventional chemotherapy [17–23]. High-risk in these studies was defined as patients having at least one or more of the following: age greater than 30 years, WBC greater than 30 ´10 9 /L at presentation, extramedullary disease, unfavorable cytogenetic abnormalities, and requiring more than 4 weeks to achieve CR. As shown in Table 17.2, DFS ranges broadly from 21% to 71%, with a 3- to 8-year follow-up. The large difference in the outcome of these phase II studies is influenced by multiple variables, including differences in patient selection, type of graft vs. host disease (GVHD) prophylaxis, and different supportive care regimens. The choice of preparative regimen may have played a smaller role since all received a total body irradiation (TBI)based conditioning regimen. Two large, prospective controlled trials have directly compared transplant with chemotherapy in patients in CR1. The French Leucemie Aigue Lymphoblastique de l’Adulte LALA 87 protocol was a cooperative study that examined the role of chemotherapy and SCT for adult ALL patients. This was a prospective, randomized study, initiated in November 1986 and completed in July 1991, which enrolled 634 newly diagnosed patients. After exclusions, 572 patients were analyzed with 10-year follow-up results. The median age of patients entered in this trial was 33 years. Patients received induction chemotherapy with cyclophosphamide, vincristine, prednisone, and one of two anthracyclines. Central nervous system prophylaxis was administered. Complete remission was achieved in 436 (76%) patients. After CR was achieved, patients older than 50 years received postremission chemotherapy. Patients between 15 and
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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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266 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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