Acute Leukemias - Republican Scientific Medical Library

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a 22.4 · CNS Relapsed in Adult Acute Lymphoblastic Leukemia 277 fer from both treatment-related mortality and a significant rate of relapse. Ultimately, few patients are longterm disease-free survivors. A major cause of this high degree of relapse is related to the modest “graft-versusleukemia” effect associated with treating ALL. Graft-versus-leukemia is the process by which the transplanted (donor) immune system eliminates residual leukemic cells and as such is a type of graft-versus-host reaction. Graft-versus-leukemia appears to be less active in ALL than in AML or CML. Supporting this concept are data from the International Bone Marrow Transplant Registry that compared identical twin (syngeneic) transplants to HLA-identical sibling transplants [16]. Graftversus-leukemia should be more pronounced in the allogeneic transplants as compared with the syngeneic transplants, and in this study there was a significantly higher relapse rate in the syngeneic transplants for AML and CML, but not for ALL. This implies that graft-versus-leukemia is less important in ALL. A second indication that graft-versus-leukemia is less active in ALL comes from an analysis of studies of donor T-cell infusions used to treat leukemia that has relapsed after allogeneic bone marrow transplant. In this study, donor lymphocyte infusions produced complete responses in 73% of patients with CML, 29% of patients with AML, and 0% of patients with ALL [17]. There is however, a mild graft-versus-leukemia effect in ALL and a report of 1132 patients with ALL demonstrated that acute and chronic graft-versus-host disease are associated with lower overall rates of relapse compared to those patients without graft-versus host disease [18]. There is significant controversy over the use and timing of allogeneic transplant in adult ALL. The results of 192 adults with ALL transplanted at the Fred Hutchinson Cancer Center report a 5-year disease-free survival of only 15% for patients transplanted in second CR or beyond [19]. Another study suggested more favorable results, but this is difficult to interpret as the results combined both pediatric and adult patients, or patients in first CR (who may already be cured) with higher-risk patients [20]. As only a small subset of patients with relapsed disease are cured with allogeneic transplant, many investigators have chosen to evaluate this modality in patients in first CR. However, two large comparisons of allogeneic transplant versus standard chemotherapy for patients in first CR have failed to demonstrate an improved survival for the transplant arm [21, 22]. In one of these studies, subset analysis suggests a benefit for certain high-risk patients [21]. However, this benefit was not confirmed in the other study [22]. Thus, currently the only patients for whom allogeneic transplant in first CR can be routinely recommended are in patients with t(9;22) and t(4;11). For other adult patients, we recommend that allogeneic transplant be reserved for second CR. Autologous transplant for adult ALL is even less effective than allogeneic transplant [23]. The extremely poor results in patients in second CR led to testing this modality in patients in first CR. However, both a nonrandomized [24] and randomized trial [25] have shown no benefit to autologous transplant compared with maintenance chemotherapy in patients in first CR. This modality should therefore be considered investigational at this time and not routinely performed in patients in first CR. 22.3 Philadelphia Chromosome-Positive Adult Acute Lymphoblastic Leukemia Philadelphia-chromosome positive (Ph+) disease carries a very poor prognosis, and long-term survival, even with high-dose chemotherapy, is rare. Thus, for patients with Ph+ disease, allogeneic transplant in first CR is commonly recommended and may be curative in a minority of patients [26, 27]. The development of imatinib (Gleevec®, formerly STI-571), a tyrosine kinase inhibitor with relative specificity for bcr-abl, has dramatically changed the treatment and outcome of patients with CML [28]. This agent also has activity in Ph+ ALL [29]. In this setting, however, it is less active than it is in CML with only 29% of relapsed or refractory patients achieving a CR [29]. Unfortunately, the median time to progression is only 2.2 months, demonstrating the development of resistance to imatinib in this patient group [30, 31]. Currently, many investigators are assessing combination therapy with imatinib and chemotherapy in both the initial treatment [32] or in the relapsed setting [33]. 22.4 CNS Relapsed in Adult Acute Lymphoblastic Leukemia CNS relapse occurs in approximately 10% of patients who have received appropriate prophylaxis. In the majority of these patients, simultaneous bone marrow relapse can be documented. In occasional patients, CNS
278 Chapter 22 · Relapsed Acute Lymphoblastic Leukemia relapse may occur without demonstrable systemic relapse (“isolated CNS relapse”); however, this event almost always predicts subsequent bone marrow relapse, and patients with isolated CNS relapse should receive reinduction chemotherapy following treatment of their CNS disease. Treatment of established CNS disease requires a combination of radiotherapy and intrathecal chemotherapy. Radiotherapy should consist of 1800– 2400 cGy (in 150–200 cGy fractions) administered to the whole brain. Higher doses should be avoided because of the risk of late toxicity and the fact that some patients may later require total body irradiation as part of a conditioning regimen for an allogeneic transplant. Despite encouraging results in children, spinal radiotherapy should be avoided in adults because the dose of radiotherapy to marrow-bearing areas subsequently limits the ability to administer necessary systemic chemotherapy. Furthermore, though this approach can help control the CNS disease it does not prolong survival as these patients will typically succumb to refractory systemic disease [34]. Intrathecal therapy with methotrexate (12 mg) for patients with established CNS disease should be administered intraventricularly, preferably via an Ommaya reservoir. Intrathecal chemotherapy can be administered as often as two or even three times per week with at least 1 day off between doses until the CSF is cleared of leukemic blasts, then twice a week for 2–3 weeks, and then twice a month for 2 or 3 additional months. Patients who develop CNS disease despite prophylaxis with intrathecal methotrexate, or those who do not clear the blasts from the CSF promptly (within two treatments) with methotrexate, should receive intraventricular therapy with cytarabine at a dose of 60 mg. 22.5 Newer Agents Given the poor overall long-term results for adult patients with relapsed ALL, newer agents are being evaluated. Clofarabine, a nucleoside analog that is a hybrid of fludarabine and cladribine, has been reported in a small group of patients (n = 12) with ALL [35]. One patient (8%) achieved a complete response that lasted 4 months. Another investigational agent, perhaps with greater promise is nelarabine, a pro-drug of ara-G. This arabinosyl analog of deoxyguanosine has shown activity [36, 37]. Nelarabine, the prodrug of ara-G, was evaluated in a phase I multicenter trial of 26 patients [36]. Com- plete (n = 5) or partial remission (n = 5) was achieved in patients; seven out of eight patients with T cell ALL, one with T lymphoid blast crisis of CML, and one with T cell lymphoma, and one with B cell CLL. Interestingly, responses were not seen in patients with B-lineage ALL. 22.6 Conclusions The treatment of adult patients with relapsed acute lymphoblastic leukemia remains a daunting task. As we gain a better understanding of the biology that distinguishes relapsing patients from those who are successfully treated, we hope to develop novel, targeted therapies to improve the initial treatment of the patients and thereby minimize the number of patients requiring treatment in the relapsed setting. Currently, the only realistic chance for long-term, disease-free survival is to induce a second CR (we favor high dose cytarabine with high dose anthracycline approach) followed by an allogeneic transplant. References 1. Woodruff R, Lister T, Paxton A, Whitehouse J, Malpas J (1978) Combination chemotherapy for hematologic relapse in adult acute lymphoblastic leukemia (ALL). Am J Hematol 4:173–177 2. Capizzi RI, Poole M, Cooper MR, et al. (1984) Treatment of poor risk acute leukemia with sequential high-dose Ara-C and asparaginase. Blood 63:694–700 3. Amadori S, Papa F, Avisati G, et al. (1984) Sequential combination high-dose Ara-C and asparaginase for the treatment of advanced acute leukemia and lymphoma. Leuk Res 8:729–735 4. Wells RJ, Feusner J, Devney R, et al. (1985) Sequential high-dose cytosine arabinoside-asparaginase treatment in advance childhood leukemia. J Clin Oncol 3:998–1004 5. Ishii E, Mara T, Ohkubo K, et al. (1986) Treatment of childhood acute lymphoblastic leukemia with intermediate-dose cytosine arabinoside and adriamycin. Med Pediatr Oncol 14:73 6. Koller CA, Kantarjian HM, Thomas D, et al. (1997) The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia 11:2039–2044 7. Giona F, Testi A, Amadori G, et al. (1990) Idarubicin and high-dose cytarabine in the treatment of refractory and relapsed acute lymphoblastic leukemia. Ann Oncol 1:51–55 8. Tan C, Steinherz P, Meyer P (1990) Idarubicin in combination with high-dose cytosine arabinoside in patients with acute leukemia in relapse. Proc Annu Meet Am Assoc Cancer Res 31:A1133 (abstr) 9. Hiddemann W, Kreutzman H, Straif K, et al. (1987) High-dose cytosine arabinoside in combination with mitoxantrone for the treatment of refractory acute myeloid and lymphoblastic leukemia. Semin Oncol 14:73
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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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a 13.5 · Prognostic Factors 173 13
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a References 175 Only patients with
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Philadelphia Chromosome-Positive Ac
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a 14.2 · Molecular Biology of the
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a 14.3 · Treatment of Ph+ ALL 181
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a 14.4 · Hematopoietic Stem Cell T
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a References 185 2. Kurzrock R, Sht
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a References 187 56. Mori T, Manabe
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a References 189 acute lymphoblasti
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192 Chapter 15 · Burkitt’s Acute
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204 Chapter 16 · Treatment of Lymp
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216 Chapter 17 · The Role of Allog
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