Acute Leukemias - Republican Scientific Medical Library

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64 Chapter 4 · Relapsed and Refractory <strong>Acute</strong> Myeloid Leukemia Fig. 4.3. Absolute difference of adjusted survival probabilities with 95% confidence interval (CI) for patients transplanted in (A) first (CR1) or (B) second complete remission (CR2) for acute myeloid leukemia (AML; Difference=Survival with autotransplant Survival with URD transplant) [88]. older patients, and patients with adverse cytogenetics to MUD-HSCT. 4.5 Investigational Agents in Relapsed and Refractory <strong>Acute</strong> Myeloid Leukemia 4.5.1 New Purine Analogs Clofarabine (2-chloro-2'-fluoro-deoxy-9-b-D-arabinofuranosyladenine) is a newer second generation adenosine nucleoside analog with less toxicity than earlier described purine analogs [41]. The drug is highly resistant to cleavage by bacterial purine nucleoside phosphorylase and is resistant to deamination by adenosine deaminase (ADA). Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, depleting the amount of intracellular dNTPs available for DNA replication and also resulting in premature DNA chain termination. In a phase II trial in relapsed and refractory patients with AML and other hematologic malignancies, an overall response rate of 48% was achieved, including a CR rate of 32% [89]. In a subsequent phase I–II trial in relapsed and refractory leukemias, predominantly AML, clofarabine was combined with cytarabine in an effort to modulate cytarabine triphosphase accumulation [90]. The overall response rate was 38% with a CR rate of 22%. Dose-limiting toxicities include reversible hepatotoxicity and rash, but no neurotoxicity. Other cytotoxic agents have been introduced. Phase I/II trials with these novel agents have demonstrated some therapeutic efficacy and currently are under further investigation in combination regimens (Table 4.4). Troxacitabine is a novel L-nucleoside analog with activity in refractory AML both as a single agent as well as when combined with cytotoxic chemotherapy [91, 92]. 4.6 Gemtuzumab Ozogamicin Gemtuzumab ozogamicin (GO) (Mylotarg) is an immunoconjugate composed of an humanized and CD33 monoclonal antibody chemically linked to a potent cytotoxic antitumor antibiotic, calicheamicin [93]. The immunoconjugate is internalized into the leukemia cell expressing CD33 and the calicheamicin is liberated intracellularly after the acid environment of the cell results in hydrolysis of the chemical linker [94]. A compilation of three phase II trials show an overall response rate of approximately 30% (15% CR by conventional criteria and another 15% CRp defined as CR, but with incomplete recovery of the platelet count) among patients in first relapse who had a relatively favorable prognosis since they had a relatively long CR1 duration and could not have had secondary AML or AML which had evolved from an antecedent hematologic disorder [95]. These results led to the approval of GO by the US FDA for older adults in first relapse who are not candidates for intensive chemotherapy [96]. In a final analysis of 277 patients in first relapse treated with GO, 26% achieved remission (13% CR and 13% CRp) with a median recurrence-free survival of 6.4 months for patients who achieved CR [96, 97]. The unique toxicity veno-occlusive disease (VOD) or sinusoidal obstructive syndrome (SOS), has been observed rarely (
a 4.6 · Gemtuzumab Ozogamicin 65 Table 4.4. Novel agents in relapsed/refractory AML Agent Class Mechanism of action Clofarabine Nucleoside analogue Gemtuzumab ozogamicin Immunoconjugates Troxacitabine Nucleoside analogue Cloretazine Alkylating agent FLT3 inhibitor Small molecule inhibitor SU5416 Small molecule inhibitor FTI Nonpeptidometricenzyme-specific linked inhibitor been incorporated in ongoing randomized trials in untreated patients with AML evaluating its benefit when combined with induction chemotherapy and as an in vivo purging agent prior to autologous HSCT. 4.6.1 Novel Alkylating Agents Cloretazine is a sulfonylhydrazine alkylating agent which has specificity for alkylation at the O 6 position Comments Inhibits RNR CR in 18% in first salvage patient with short CR1 and 75% with long CR1, 38% and 50% in second or greater salvage Phase II trials as single agent or in combination with Ara-C, particularly in older adults underway [90, 91] Randomized trials of clofarabine compared to conventional chemotherapy are ongoing Antitumor Antibiotic Calicheamicin OR 30% in older adults in late first relapse [93–97] Randomized trials of conventional chemotherapy +/– GO and as in vivo purge prior to autologous HSCT underway Inhibits RNR OR 18% in refractory AML, combination studies show anti-leukemia activity; causes unique hand–foot syndrome [91, 92] DNA damage Very modest activity in relapsed AML with short CR1 duration Phase III trials underway evaluating chemotherapy +/– cloretazine [100, 101] Inhibits TK Reduction in blasts in blood and marrow, but rare CR Phase III trials evaluating chemotherapy +/– inhibitor planned [102] Inhibits VEGF receptor Inhibits farnesyl protein transferase Modest clinical efficacy as a single agent [103] Modest clinical activity, but with some CRs [104] Phase III trial in older adults in CR1 or any age in CR2 after consolidation as maintenance underway Oblimersen Antisense Inhibits bcl-2 Can be combined with chemotherapy [105] Decitabine Nucleoside analoghypomethylating agent Removes methyl groups from DNA Induces some CRs [106] CR, complete remission; ara-C, cytosine arabinoside; RNR, ribonucleotide reductase; FLT3, fms-like tyrosine kinase3: TK, tyrosine kinase; VEGF, vascular endothelial growth factor; OR, overall response; FTI, farnesyltransferase inhibitor. of guanine distinguishing it from other alkylating agents [100, 101]. Very modest activity in high-risk relapsed AML patients (CR1 duration < 6 months), has been demonstrated with a CR2 rate of 4% [101]. This agent may prove more effective when combined with other agents. In a phase I trial of patients with generally advanced AML of cloretazine combined with intermediate-dose ara-C, a CR rate of 10% and CRp rate of 15% were observed [100]. A prospective randomized trial for patients in first relapse comparing conven
Page 1 and 2: E.H. Estey · S.H. Faderl · H. M.
Page 3 and 4: E. H. Estey Department of Leukemia
Page 5 and 6: VI Table of Contents 14 Philadelphi
Page 7 and 8: VIII Contributors S. H. Faderl Depa
Page 9 and 10: X Contributors D. Wartenberg Depart
Page 11 and 12: Therapy of AML Elihu Estey Contents
Page 13 and 14: a 1.2 · Standard Therapy 3 Table 1
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Page 17 and 18: a 1.2 · Standard Therapy 7 tween G
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Page 29 and 30: a References 19 6-thioguanine in th
Page 31 and 32: Acute Myeloid Leukemia: Epidemiolog
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Page 41 and 42: Relapsed and Refractory Acute Myelo
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Page 61 and 62: Part II - Acute Lymphoblastic Leuke
Page 63 and 64: 78 Chapter 5 · Acute Lymphoblastic
Page 79 and 80: Molecular Biology and Genetics Meir
Page 81 and 82: a 6.3 · Structural Aberrations 97
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Page 87 and 88: a References 103 clear that homozyg
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Page 91 and 92: a References 107 122. Lennard L, Li
Page 93 and 94: Diagnosis of Acute Lymphoblastic Le
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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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230 Chapter 18 · The Role of Autol
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238 Chapter 19 · Novel Therapies i
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248 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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