Acute Leukemias - Republican Scientific Medical Library

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a 19.2 · New Chemotherapy Agents 239 and its liposomal cousin. Whereas the half-life of free vincristine is only 10 minutes, it is up to 8 h with the liposomal preparation [6]. Liposomal vincristine has been studied successfully in lymphoma salvage, as part of the CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) plus rituximab regimen in Non-Hodgkin’s lymphoma (NHL) patients, and in early clinical studies in ALL salvage. Liposomal vincristine was well tolerated and achieved a response rate of 35% in patients with relapsed and refractory NHL [7]. In a more recent update important predictors of response included number of prior regimens and sensitivity to the most recent treatment regimen. Response rates of up to 64% were reported in those patients with sensitive disease and not more than two prior regimens [8]. Rodriguez et al. substituted liposomal vincristine for free vincristine and investigated the liposomal preparation as part of the CHOP plus rituximab combination in patients with previously untreated NHL [9]. Patients received standard doses of CHOP, which included liposomal vincristine at 2 mg/m 2 (no dose capping). Of 68 patients who were evaluable for response 63 (93%) responded, which included 62 patients with complete remission (CR), one with unconfirmed CR and one patient with partial response. At a median follow up of 29.5 months, median progression-free survival (PFS) and overall survival (OS) have not been reached. The treatment was well tolerated with only mild neurotoxicity. In a small study in ALL of single-agent liposomal vincristine at 2 mg/m 2 given every 2 weeks, responses occurred in two of 14 (14%) evaluable relapsed/refractory patients [10]. In a more recent phase I trial for patients with relapsed and refractory ALL, liposomal vincristine (dose range 1.5 mg/m 2 to 2.25 mg/m 2 ) weekly for four doses per course was given in combination with pulse dexamethasone (40 mg daily on days 1–4 and 11–14) [11]. Of 14 evaluable patients, 4 (29%) achieved CR extending through all dose levels, and another two (14%) achieved hematologic improvement. Almost all patients experienced peripheral neuropathy, which did not exceed grade 2 on the NCI Common Toxicity scale. The study is ongoing. Once the MTD has been defined, substitution of vincristine for the liposomal preparation in ALL induction protocols such as the hyper-CVAD regimen is planned. 19.2.2 Nucleoside Analogs Since their establishment as antitumor drugs in the 1960s, nucleoside analogs have been among the most active agents for patients with cancer. In addition to the established and more traditional nucleoside analogs such as cytarabine, fludarabine, cladribine, or pentostatin, new nucleoside analogs are emerging that demonstrate additional metabolic properties and mechanisms of actions, and their activity is currently evaluated in clinical trials including in patients with ALL [12]. Nelarabine (compound 506U78, ara-G) is the water-soluble prodrug of the deoxyguanosine analog guanosine arabinoside (ara-G) [13]. Nelarabine is not active by itself and requires conversion to ara-G by the enzyme adenosine deaminase, which is an efficient enough process to result in cytotoxic levels of ara- GTP in circulating leukemia cells. It has been demonstrated that ara-GTP is accumulated at higher levels in T lymphoblasts than in myeloblasts or B lymphoblasts. In addition, it has been shown in human leukemia cell lines that cytotoxicity to T lymphoblasts was increased with greater accumulation and more prolonged retention of ara-G in these cells [14–17]. Several early clinical trials of nelarabine have been conducted in refractory acute and chronic leukemias. Using a schedule of 1200 mg/m 2 or more daily for up to 5 days, response rates of 40–50% have been reported in refractory T-cell ALL. At most of these schedules, neurotoxicity (including seizures, obtundation, ascending paralysis) was the DLT and the maximum-tolerated dose (MTD) in adults has been established at 40 mg/kg/day for 5 days [18]. Alternative schedules and doses are therefore being explored. To reduce the risk of neurotoxicity, the CALGB and SWOG investigated a nelarabine schedule of 1.5 g/ m 2 /day given on days 1, 3, and 5 every 21 days [19]. Forty patients (22 ALL and 18 lymphoblastic lymphoma [LL]) were enrolled. All patients were refractory to at least one induction regimen or were in first or subsequent relapse without demonstrable CNS disease. Of 21 evaluable ALL patients, the OR was 38% (including six CR patients). For the group of LL patients, 24% responded (including four CR) for an overall response rate of 38% in 38 evaluable patients. Myelosuppression was the main toxicity with minimal neurotoxicity reported. The median DFS for the CR patients was 9.8 months. The POG/CCG Intergroup investigated nelarabine in patients with relapsed and refractory T-cell
240 Chapter 19 · Novel Therapies in <strong>Acute</strong> Lymphoblastic Leukemia malignancies < 21 years of age [20]. Depending on salvage status, doses of 400 mg/m 2 up to 650 mg/m 2 daily for 5 days every 21 days were used. The initial dose of 1.2 g/m 2 daily proved too neurotoxic. Among patients with T-cell leukemia in first relapse (650 mg/m 2 ), response rates exceeded 50% and were lowest in those with extramedullary relapse (400 mg/m 2 ). Although nelarabine was well tolerated at these dose levels, peripheral neuropathy remained the most significant adverse event. The efficacy of nelarabine in T-cell leukemias notwithstanding, doses and schedules need to be further investigated in particular subsets of adults and children. Combinations of nelarabine with other nucleoside analogs such as fludarabine based on biochemical modulation of intracellular ara-GTP levels have been reported [21]. Clofarabine is a second-generation nucleoside analog that has been synthesized as a rational extension of the experience with other deoxyadenosine analogs such as fludarabine and cladribine. After cellular uptake, clofarabine is converted to the monophosphate compound by the enzyme deoxycytidine kinase whereby phosphorylation of clofarabine by deoxycytidine kinase is substantially more efficient than that of fludarabine or cladribine. Furthermore, retention of the triphosphate form of clofarabine in cells is also longer than that of fludarabine and cladribine. Clofarabine is active by inhibition of DNA synthesis, ribonucleotide reductase (resulting in depletion of normal deoxynucleotides and increased DNA incorporation of the analog referred to as self-potentiation), and various DNA polymerases [22]. In a phase I study of clofarabine in children with relapsed and refractory acute leukemias, the MTD has been established at 52 mg/m 2 daily for 5 days every month with the DLT defined by reversible hepatotoxicity and skin rash at doses of up to 70 mg/m 2 daily [23]. Out of 17 patients with heavily pretreated ALL, four (24%) achieved CR and one (6%) PR, which made for an overall response of 30%. In a subsequent larger phase II study, which included 49 children with ALL, 31% responded (six CR, four CRp, five PR) with a median survival of 42 weeks (range 7 to 63.1 +) for these patients [24]. Among the patients who were refractory to the last prior chemotherapy, 23% (7/30) patients with ALL responded. Based on the positive experience and the response rates in pediatric ALL, clofarabine received Food and Drug Administration (FDA) approval in December 2004 for children with relapsed/refractory ALL who have at least received two prior regimens. Phase I studies in adults with acute leukemias defined the MTD for clofarabine at 40 mg/m 2 /day [25]. Less experience exists with clofarabine in adult ALL. A large phase II study of 62 patients with relapsed acute leukemias included 12 ALL patients, two-thirds of whom received clofarabine in their second or subsequent salvage [26]. Two patients responded (one CR, one CRp) for an overall response of 16%. The complete responder had Ph-positive disease and was primary refractory to induction with the VAD regimen. The potential of clofarabine for adult ALL remains to be explored. Clinical studies of clofarabine combinations (e.g., with cyclophosphamide) are underway. 19.2.3 Epigenetic Therapy Aberrant methylation of promoter-associated CpG islands and silencing of tumor-related genes due to hypermethylation is an epigenetic modification that is frequently observed in human cancers and leukemias [27]. A particularly high frequency of this process has been observed in ALL both at presentation and at relapse where methylation of genes can be demonstrated in up to 80% of patients [28, 29]. Several groups have been able to identify a number of genes involved in hypermethylation, which identified subsets of patients with a “hypermethylator” phenotype that has prognostic significance. Roman-Gomez et al. evaluated the methylation status 15 genes in 251 ALL patients [30]. In more than 75% of the patients, at least one gene was hypermethylated with ³ 4 genes hypermethylated in about 36%. Although there was no difference in CR rates among the groups with variable numbers of genes affected, DFS and overall survival were significantly different: 75.5% and 66.1%, respectively, for the nonmethylated group compared to only 9.4 and 7.8% for patients with ³4 involved genes (p < 0.0001 and p
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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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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 Subject Index 291 CREB, see enhan
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a Subject Index 293 MUD, see matche
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