Acute Leukemias - Republican Scientific Medical Library

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a 17.4 · Philadelphia Chromosome-Positive ALL 219 nine remaining alive in CR with a median follow-up of 12 months. Among ten patients ineligible for SCT, one relapsed after 12 months, two died in CR from comorbid conditions at 15 and 16 months, and five remained in continuous CR for a median of 20 months [36]. Although this is an early study with very short followup, these results are very encouraging for a subset of patients with a traditionally very poor prognosis. Data from the MRC UKALL XII/ECOG E2993 study described earlier revealed similar poor results for Ph+ patients treated with chemotherapy only. In this ongoing, prospective, randomized study, 167 Ph+ patients were treated on the MRC UKALL XII/ECOG E2993 protocol between 1993 and 2000. Seventy-two patients received a matched-related or unrelated donor transplant in CR1, while seven received an autologous transplant and 88 received chemotherapy due to lack of donors. As expected, the 5-year EFS and OS were significantly higher for the allogeneic transplant group, 36% and 42%, respectively, compared to 17% and 19% for the nonallogeneic transplant groups [37]. These results suggest that the presence of the Ph chromosome is most detrimental to maintaining long-term remission, and underscore the need for long-term follow-up of ongoing studies with imatinib. Until long-term results are obtained, all Ph+ patients should still receive an allogeneic SCT in CR1 if a donor is available. Disease outcome from a series of single-center retrospective studies are listed in Table 17.4 [19, 38–40]. It is difficult to draw conclusions from these small series that vary considerably with respect to type of patient (CR1 or beyond), type of preparative regimen, GVHD prophylaxis, and supportive care. The reported DFS rate varies widely between 20% to 80%, and it is difficult to determine if a particular preparative regimen is superior. Generally, data from most series suggest that Ph+ patients fare best when transplanted in CR1. Follow-up from the prospective MRC UKALL XII/ECOG E2993 study is eagerly anticipated. Table 17.4. Allogeneic transplantation for Ph+ ALL It is hoped that the incorporation of imatinib into the transplant conditioning regimen or early posttransplant will further improve results. The Cancer and Leukemia Group B (CALGB), in combination with the Southwest Oncology Group (SWOG) are enrolling patients in a Phase II trial of sequential chemotherapy, imatinib, and allogeneic or autologous SCT for adults with newly diagnosed Ph+ ALL. The primary objectives of this study will be to determine the ability of imatinib to produce a complete molecular response (achieve BCR/ABL- status by RT-PCR) following sequential chemotherapy, imatinib therapy, and transplantation, and to determine the ability of imatinib to improve DFS and OS in this high-risk group of patients. The safety and efficacy of concurrent imatinib administration with high dose chemotherapy is being investigated in blast phase CML patients currently enrolled in clinical trials at MD Anderson Cancer Center, and results may be applicable to Ph+ ALL patients. The feasibility of alternative donor transplants has also been investigated in Ph+ ALL patients in efforts to provide allogeneic transplantation to patients who lack a matched sibling. At the Fred Hutchinson Cancer Research Center, matched unrelated donor (MUD) transplantation was investigated in 18 patients with Ph+ ALL between 1988 and 1995. The study included children and adults, with the median age being 25 years. Seven patients were in CR1, one in CR2, three in first relapse, and seven with advanced disease. The preparative regimen involved TBI and cyclophosphamide. Six patients who were transplanted in CR1, one in CR1, and two while in second remission remained leukemia-free at a median follow-up of 17 months. The probability of LFS at 2 years was 49%, similar to rates reported for matched-sibling-SCT [41]. However, it must be emphasized that this was a highly selected population of relatively young patients. Too few adults with Ph+ ALL have received cord blood or haploidentical donor transplants to comment on results. Study No. pts Med. age (years) Prep. regimen 3-year DFS% Stockschlader, 1995 [39] 10 31 VP-16/CY/TBI 46 Dunlop, 1996 [40] 11 27 TBI-based 21.8 Snyder, 1999 [38] 23 30 VP-16/fTBI 65 (SCT before 1992) CY, cyclophosphamide; TBI, total body irradiation; fTBI, fractionated TBI; VP-16, etoposide. 81 (SCT after 1992)
220 Chapter 17 · The Role of Allogeneic Stem Cell Transplantation in the Therapy of Adult <strong>Acute</strong> Lymphoblastic Leukemia (ALL) Donor lymphocyte infusion (DLI) has also been investigated in patients with Ph+ ALL. DLI is most effective as treatment for Ph+ chronic phase CML, but has little benefit for patients with either myeloid or lymphoid blast crisis. Although peptides derived from bcr-abl may be immunogenic, the immunologic target of DLI is unknown and minor histocompatibility antigens and overexpressed myeloid lineage related proteins might be involved. DLI has had very limited efficacy in Ph+ ALL [42, 43]. It is not known whether this disparity in efficacy stems from differences in the immunogenicity of the p190 BCR/ABL (most Ph+ ALL) vs. the p210 BCR/ABL (most CML), differences in growth kinetics of Ph+ ALL relapse (high tumor burden) vs. those in CML (lower tumor burden), or other disease specific factors. Interestingly, in a study of 11 patients, including one with Ph+ ALL, second allogeneic PBSC transplants from the original donor were administered for treatment of relapse. All patients achieved CR, but responses were not durable. The patient with Ph+ ALL achieved a complete clinical and molecular response, but died at 12 weeks due to CNS relapse. This was the only site of disease at time of death [44]. 17.5 Factors Influencing Transplant Outcome 17.5.1 Preparative Regimens 17.5.1.1 Radiation-based Several different preparative regimens for allogeneic SCT have been described in attempts to decrease transplant related mortality (TRM) and improve DFS. The most widely used regimen is the combination of total body irradiation (TBI) and cyclophosphamide developed by Thomas and colleagues. TBI can be administered as single dose, or fractionated over 3–5 days. A comparative analysis of fractionated-dose vs. singledose TBI in adult ALL patients showed a significantly higher TRM in the single-dose group (p = 0.017), but an increase in the relapse rate of the fractionated-dose group; consequently, there were no differences in the overall LFS between the two groups [21]. The Minnesota Group compared TBI/cyclophosphamide with TBI/Ara- C in a study including both adults and children, and found no outcome difference in regards to toxicity or outcome [45]. The City of Hope group studied fractionated TBI with etoposide followed by SCT in patients with advanced leukemia. A Phase I/II trial indicated that etoposide at 60 mg/kg is the maximum tolerated dose when combined with TBI. In that study, 36 ALL patients were treated; 20 had relapsed disease. The DFS was 57%, with a 32% relapse rate suggesting that the regimen has significant activity in advanced ALL [46]. Novel methods to allow selective delivery of radiation to sites of leukemia without increasing systemic toxicity are currently under investigation. One method with great potential is the incorporation of radiolabeled monoclonal antibodies (MoAb) into the conditioning regimen. A Phase I transplant trial using 131 I-labeled anti-CD45 antibody combined with cyclophosphamide at 120 mg/kg and 12-Gy TBI was recently published [47]. All patients had advanced hematologic malignancies. The dose limiting toxicity was grade III/IV mucositis. Nine patients with ALL (five with relapsed/refractory ALL; four in CR2 or CR3) received allogeneic (six patients) or autologous (3 patients) transplants using this preparative regimen; three patients were diseasefree 19, 54, and 66 months posttransplant. A more recent study evaluated the feasibility of using 188 rhenium ( 188 Re)-labeled anti-CD66 in combination with standard high-dose chemotherapy/TBI (12 Gy) in 50 advanced leukemia patients, including 11 with ALL, undergoing allogeneic or autologous SCT. All patients achieved primary engraftment. After a median follow-up of 11 months, 28/50 (56%) patients were in CR, nine (5%) patients relapsed, and 13 (7%) died from treatment-related causes [48]. The ultimate benefits of this approach with respect to safety and improvements in survival will be defined by Phase II studies for patients with ALL. Much more clinical data has been gathered for nonradiolabeled MoAbs as discussed below. 17.5.1.2 Nonradiation-based Nonradiation-containing regimens, most commonly busulfan and cyclophosphamide, have been investigated in hopes of decreasing radiation-related complications. Fractionated TBI/etoposide was compared with busulfan/cyclophosphamide in a prospective, randomized study conducted by the Southwest Oncology Group (SWOG 8612). One hundred twenty-two patients with leukemia beyond CR1 received either FTBI/etoposide or busulfan/cyclophosphamide in preparation for SCT. One hundred fourteen (93%) proceeded to SCT. All patients received cyclosporine and prednisone for post-
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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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270 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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