238 Magda Melchert, Jeffrey Lancet the selection of patients upon whom these results are based. Epidemiology Incidence It is clear that AML is a disease that primarily affects older individuals. In the USA, the incidence peaks at a rate of 20–25 per 100 000 in people over age 75, compared with less than 2.5 per 100 000 in people under age 55 (Fig. 19.1). Unfortunately, the mortal- ity rate closely parallels the incidence in older indi- viduals, speaking to the high degree of lethality of the disease, despite its relatively low incidence com- pared with other malignancies. Environmental exposures There are few known causative environmental factors in AML, though exposure to certain tox- ins has been associated with an increased risk of disease. Chronic benzene exposure is one of the best-described environmental risk factors for the development of AML [8–10]. Another environmental exposure to which the development of AML has been implicated is external radiation, which may result in a two- to six fold increase in relative risk [10–12]. Systemic exposure to a multitude of chemotherapeu- tic agents, including alkylating agents, epipodophyl- lotoxins, and topoisomerase II inhibitors have been clearly associated with an increased risk for AML [13– 15]. Such treatment-related AML is characterized by cytogenetic anomalies in chromosomes 5, 7, and 11, and is nearly invariably associated with a very poor prognosis [15–17]. Hydroxyurea, a commonly used agent for several myeloproliferative diseases, may also impart an increased risk for the development of AML with the deletion of the short arm of chromosome 17 [18]. Several reports have also clearly indicated an increased risk of secondary AML and MDS following high-dose therapy and autologous transplantation for diseases such as non-Hodgkin lymphoma and multiple myeloma [13,19]. Finally, cigarette smoking appears to impart a modestly increased risk for AML, and this risk appears to be exacerbated in adults over age 60 [10,20]. Diagnosis and classifi cation AML is a disease in which diagnosis and classi- fi cation are made upon morphologic, and more recently cytogenetic, criteria. A comparison of the Figure 19.1 Incidence of AML in the US population by age and sex, 1969–2002 [7]. See color plate section. 32.5 30 27.5 25 22.5 20 17.5 15 12.5 10 7.5 5 2.5 0 Age at diagnosis 00 01–04 05–09 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85ϩ Rate per 100 000 Male and female Male Female Acute myeloid leukemia 239 French–American–British (FAB) classifi cation sys- tem and the more recent World Health Organization (WHO) system is shown in Table 19.1. One impor- tant difference in the WHO system is the lowering of the threshold for diagnosis of AML from 30% to 20% blasts in the bone-marrow aspirate or periph- eral blood. This change subsequently eliminated the former FAB-delineated MDS category of refrac- tory anemia with excess blasts in transformation (RAEB-T). One category in the WHO classifi cation system also specifi es AML with multilineage dys- plasia. Since a signifi cant proportion of AML in the elderly is thought to arise from MDS, the WHO sys- tem may be particularly relevant for older patients. Another category, AML with recurrent cytogenetic abnormalities, refers to those cases with transloca- tions involving chromosome 11q23, between 15 and 17 (acute promyelocytic leukemia), 8 and 21, 16 and 16, and chromosome 16 inversion. This category of AML occurs primarily in younger individuals [22]. Biologic characteristics of AML in elderly patients Cytogenetic abnormalities A clonal disorder, AML is characterized by molecular lesions that are often recognized as chromosomal Table 19.1. Comparison of French–American–British (FAB) and World Health Organization (WHO) classifi cation of AML [21]. FAB classifi cation WHO classifi cation M0 AML, minimally differentiated AML with recurrent cytogenetic abnormalities у30% blasts bone marrow у20% blasts bone marrow t(8;21)(q22;q22) (AML1/ETO) inv(16)(p13q22) or t(16;16)(p13;q22) (CBFβ/MYH 11) t(15;17)(q22;q12) (PML/RARα), APL 11q23 (MLL) M1 AML, without maturation AML with multilineage dysplasia у30% blasts bone marrow у20% blasts bone marrow Following MDS or MDS/MPD Without MDS or MDS/MPD, but with dysplasia involving Ͼ50% cells in 2 or more lineages M2 AML, with maturation AML and MDS, therapy-related у30% blasts bone marrow Alkylating agent/radiation-related type Topoisomerase II inhibitor-related type Others M3 acute promyelocytic leukemia (APL) AML, not otherwise categorized у30% blasts bone marrow у20% blasts bone marrow M4 acute myelomonocytic leukemia у30% blasts bone marrow M5 acute monoblastic leukemia у30% blasts bone marrow M6 acute erythroleukemia у30% blasts bone marrow M7 acute megakaryoblastic leukemia у30% blasts bone marrow 240 Magda Melchert, Jeffrey Lancet aneuploidy or translocations. The specifi c leukemic karyotype can then be prognostically categorized further into favorable, intermediate, or unfavor- able subtypes (Table 19.2). The frequency of spe- cifi c leukemic karyotypes as well as the prognostic category differs between older adults and younger ones [23,24]. Specifi cally, cytogenetic abnormali- ties involving t(15;17), t(8;21), and inversion 16 [t(16;16)] are rarely encountered in older adults with AML [23,25–27]. Conversely, the frequency of specifi c karyotypes that fall within the unfavorable subgroup, such as full or partial deletions of chro- mosomes 5 and 7, trisomy 8, or 11q23, are higher in the elderly AML setting [23–27]. Additionally, AML secondary to previous exposure to cytotoxic chemo- therapy or environmental carcinogens appears to be more frequently associated with abnormalities of chromosomes 5 and 7. Topoisomerase II inhibi- tors such as etoposide, mitoxantrone, and doxo- rubicin have shown a strong association with the mixed-lineage leukemia (MLL) gene at 11q23 [28]. Complex karyotype is also more frequently seen in older adults, and consistently confers an inferior complete remission rate and long-term survival [23,29]. Molecular anomalies In the last decade, several other molecular abnor- malities have been found to be associated with AML. These markers have been identifi ed in both older and younger AML patients, and have been identi- fi ed as prognostically important only in younger patients with normal karyotype. FMS-like tyrosine kinase (FLT3) is expressed on early hematopoietic and lymphoid progenitors, and appears to play an important role in myeloid differentiation and stem- cell survival [32]. Internal tandem duplications of the FLT3 gene (FLT3-ITD) involving the juxtamembrane region have now been described to be present in 17–34% of patients with AML [32–34]. A point muta- tion in codon 835 of the FLT3 gene has also been discovered and involves the activating loop of the tyrosine kinase domain (TKD), although it is detected with considerable lower frequency [35]. Using mouse models, transfection of the FLT3-ITD mutation into myeloid cell lines induces leukemia-type disease in syngeneic mice [36]. Further in-vitro studies have shown that FLT3-ITD causes a ligand-independent receptor dimerization with subsequent constitutive activation of Ras, MAP kinase, and Stat5 pathways, Table 19.2. Prognostic classifi cation of karyotype analysis [30,31]. Favorable Intermediate Unfavorable Inv(16), t(16;16), del(16q) Normal karyotype Monosomy 5, 5q– t(8;21) Trisomy 6 Monosomy 7, 7q– t(15;17) –Y Trisomy 8 Del(12p) Abn 3q Other non-complex Abn 9q karyotype 11q23 (MLL) t(9;22) 20q– 21q– 17p t(6;9) Complex karyotype (involving 4 or more unrelated mutations) Acute myeloid leukemia 241 and thus unregulated cell proliferation [36,37]. AML patients with FLT3-ITD and TKD mutations often present at diagnosis with higher white blood cell counts, a higher percentage of blasts, higher LDH, and more commonly with de novo AML [37]. While complete remission rates are generally unaffected by the presence of FLT3 abnormalities, a signifi cantly inferior disease-free survival and overall survival have been described by most authors [32,37–39]. Also of considerable importance in cytogeneti- cally normal AML is the presence of nucleophosmin member 1 gene (NPM1) mutations. Heterozygous mutations involving exon 12 of the NPM1 gene result in translocation of the nucleophosmin gene product from the nucleus to the cytoplasm [40]. Concurrent FLT3-ITD mutations can be identi- fi ed in up to 40% of patients with mutated NPM1. Increased bone-marrow blast percentage, female sex, increased lactate dehydrogenase levels, higher white blood cell count, lower platelet count, and low or absent CD34+ expression have all been associ- ated with NPM1 mutations [40,41]. Also function- ally important to normal myeloid maturation is the gene CCAAT/enhancer-binding protein α (CEBPA). Mutations of this gene are also present in increased frequency in patients with normal cytogenetics, in approximately 15–20% of cases. Mutated CEBPA has been associated with lower platelet counts, higher percentages of peripheral blood blasts, less extramedullary involvement and less lymphade- nopathy [40,42]. Another molecular abnormality that has been described with considerable frequency in AML is the Ras proto-oncogene. The majority of Ras muta- tions involve point mutations at codons 12, 13, and 61, leading to constitutive activation of Ras protein. Mutations at one of the three functional Ras genes leads to decreased GTPase activity of the Ha-, Ki-, or N-ras proteins, which in turn causes leukemic transformation [43,44]. N-ras has been detected in 15–30% of AML samples, and multiple groups have attempted to stratify prognostically according to the presence of one of these mutations. Despite evidence that the presence of the N-ras proto- oncogene in patients with MDS confers a higher risk of progression to AML and inferior overall survival [45], the majority of clinical correlates have failed to show an unfavorable outcome in patients with AML [38,43,46,47]. Of considerable interest in recent years is the multi- drug resistance phenotype, with the associated gene (MDR1) located on the long arm of chromosome 7. MDR1 encodes a 170 kD glycoprotein, or P-glyco- protein (Pgp), that functions as an ATP-dependent effl ux pump. In-vitro models have shown that over- expression of Pgp has led to increased cellular export of anti-neoplastic drugs, including anthracyclines, vinca alkaloids, epipodophyllotoxins, and taxol [48]. The MDR1 phenotype in elderly patients with AML confers a resistance to anthracycline chemotherapy with a signifi cantly inferior complete remission rate, disease-free survival, and overall survival [27,49]. In the SWOG 9031 trial, 71% of patients greater than age 55 exhibited the MDR1 phenotype, while in the SWOG 8600 trial, with patients younger than 55, the incidence of MDR1 overexpression was approxi- mately 30% [27]. The increased incidence of Pgp overexpression in the elderly supports the fi nding that conventional induction therapy in the elderly is less effi cacious than in younger adults. Therapeutic strategies to inhibit Pgp cellular export of anthra- cyclines have been investigated, with compounds such as cyclosporine, quinine, and PSC-833, with variable success [49,50]. These will be discussed in further detail later in the chapter. Treatment While the majority of patients with AML are con- sidered to be elderly, their response to standard chemotherapy has been historically poor, with lower response rates and increased treatment-related mor- tality. Complete remission (CR) rates for patients younger than age 55–60 generally range 60–80%, while CR rates in elderly patients are reported in most studies as 30–50% (Table 19.3). Tolerability of intensive induction therapy has also been sub- optimal, due in part to the high risk of infection with prolonged cytopenias and also to the prevalence of 242 Magda Melchert, Jeffrey Lancet signifi cant comorbidities in the elderly [51]. The fre- quency of early death in younger patients exposed to standard induction chemotherapy has been as high as 10–20%, but it is 20–40% in the elderly. However, treatment-related mortality rates continue to decline as supportive care measures improve with time. In order to increase remission rates and minimize toxic- ities, various strategies to optimize induction therapy for the elderly have been explored. Some of the stud- ies aimed at improving chemotherapy have utilized less intensive regimens, alternative dosing or choice of anthracyclines, addition of alternative chemother- apies, and use of hematopoietic growth factors both as priming and as supportive care. Finally, several new targeted agents have been explored for the treat- ment of patients unable to tolerate standard inten- sive therapy, or in the salvage chemotherapy setting. Supportive care versus induction chemotherapy Given the high treatment-related mortality and suboptimal response to chemotherapy, several groups in the 1980s evaluated the benefi t of induc- tion chemotherapy in elderly patients with AML [63–65]. However, only one study by the EORTC was designed prospectively and provided a basis for further studies of intensive chemotherapy in eld- erly patients [65]. In this trial, elderly AML patients who were randomized to supportive care achieved a median overall survival of 11 weeks, versus a 22-week median survival for those receiving inten- sive chemotherapy. This study confi rmed that elderly patients have an improved survival with intensive chemotherapy when compared to sup- portive care alone. Induction chemotherapy A standard regimen for induction chemotherapy in elderly AML patients is cytarabine 100 mg/m 2 by con- tinuous intravenous infusion (CIVI) over seven days with daunorubicin 45–60 mg/m 2 daily for three days (7 ϩ 3 regimen). In order to identify a more effective induction regimen with additional agents, the Medical Research Council (MRC) AML11 trial randomized Table 19.3. Comparison of outcomes for induction therapy for AML in younger (Ͻ55–60) and older (Ͼ55–60) patients. Age Ͼ55–60 Age Ͻ55–60 Trial Year CR (%) ED (%) CR (%) ED (%) AMLCG [52] 1985 51 33 68 25 CALGB [53] 1987 41 31/45 65 21 CALGB [54] 1991 41 43 69 15 SECSG [55] 1992 53/63 NA 63/79 NA CALGB [56] 1994 47 31 71 13 BMRC [57] 1996 46 30 73 12 IAMLSG [58] 1997 64 a NA 74 a NA SWOG [27] 1997 45 32 NA NA SWOG [59] 1998 NA NA 70 7 MRC: AML10, 11 [23,60] 2001 43 20 59 8 SWOG [61] 2002 34/43 17 NA NA ECOG [62] 2004 42 17 NA NA CR, complete remission; ED, early death; NA, not available; a stratifi ed by age Ͻ50 or у50 years Acute myeloid leukemia 243 over 1000 elderly patients to two cycles of one of three regimens: daunorubicin, cytarabine, thioguanine (DAT) vs. cytarabine, daunorubicin, etoposide (ADE) vs. mitoxantrone and cytarabine (MAC) [25]. Patients receiving DAT experienced a statistically signifi cant improvement in CR when compared to ADE or MAC, although fi ve-year overall survival rates were similar in all three induction groups. Given these results, it is reasonable to conclude that the addition of thiogua- nine can improve CR rates in the elderly, although no benefi ts are seen with respect to survival. The anthracycline idarubicin has been shown in studies with younger patients to have modestly superior CR rates, although also without clear ben- efi ts in overall survival [55,66]. Multiple groups have investigated the benefi ts of mitoxantrone or idarubicin in older patients, with variable improvements in remission rates. A large randomized controlled trial by ECOG was recently reported evaluating the optimal choice of anthra- cycline [62]. Over 350 AML patients older than 55 years received cytarabine in addition to one of three anthracyclines: idarubicin 12 mg/m 2 (IA) vs. dauno- rubicin 45 mg/m 2 (DA) vs. mitoxantrone 12 mg/m 2 (MA). In the subset of patients aged 55–70, there was a signifi cant improvement in CR with idarubicin, but this benefi t diminished in patients over the age of 70. Furthermore, there was no signifi cant differ- ence between the three regimens with respect to disease-free survival (DFS) or overall survival (OS). Given the lack of clear benefi t in survival with other anthracyclines, daunorubicin remains the standard anthracycline of choice in elderly patients when given with cytarabine. The optimal dose of daunorubicin in elderly patients has been heavily investigated, with most doses ranging from 30 mg/m 2 to 60 mg/m 2 for 1–4 days. While it is diffi cult to make direct comparisons among various studies, a large metanalysis of over 2000 patients found a clear benefi t in terms of CR rates and fi ve-year DFS for patients who received at least 90 mg/m 2 total dose of anthracycline [67]. The incidence of early death in these two groups was essentially identical. Hence there is no clear benefi t to reducing the daunorubicin dose in the elderly. With a goal of minimizing treatment-related mor- bidity and mortality, less intensive chemotherapy regimens have also been explored [61,68,69]. In a large phase III SWOG study comparing the standard therapy of daunorubicin and cytarabine with mitox- antrone and etoposide, the non-cytarabine arm was inferior with lower CR rates and lower two-year OS [61]. Furthermore, a less intensive regimen of oral idarubicin and etoposide resulted in a 36% CR rate in elderly patients who would not otherwise receive standard therapy [70]. Another minimally toxic regimen consists of low-dose cytarabine 10 mg/m 2 subcutaneously, twice a day for 7–14 days, in addi- tion to etoposide 100 mg daily for 3 days and either low-dose mitoxantrone or 6-thioguanine. A 50% CR rate was reported with this well-tolerated protocol [71]. Cytarabine as a single agent has also been used in the treatment of elderly AML patients unable to receive standard chemotherapy. When compared to hydroxyurea (Hydrea), there was a signifi cant improvement in CR rates and OS [72]. For patients with comorbidities precluding the use of intensive chemotherapy, a low-dose therapy regimen may be a reasonable alternative to offer patients. However, given the data supporting the use of intensive chemotherapy in “fi t” elderly patients, they should not be recommended universally to patients older than age 60. Growth factors Leukemic blasts of elderly patients with AML are more commonly resistant to standard chemo- therapy, as evidenced by inferior remission rates. Priming of the leukemia with growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-monocyte colony-stimulating fac- tor (GM-CSF), has been of interest to several groups [62,73]. Both G-CSF and GM-CSF have been shown to alter the cell-cycle kinetics of the leukemia blasts, rendering them more susceptible to agents such as cytarabine, which has cell-cycle-dependent cyto- toxicity [74]. In younger patients, the addition of G-CSF to induction chemotherapy with idaru- bicin and cytarabine, followed by amascrine and 244 Magda Melchert, Jeffrey Lancet cytarabine, resulted in signifi cant improvements in DFS and OS [73]. However, a large ECOG study revealed no CR or survival benefi t from GM-CSF priming in elderly AML patients given just prior to induction chemotherapy [62]. It appears unlikely that growth-factor priming has any benefi t in leuke- mia outcomes, but delays in the initiation of induc- tion chemotherapy may adversely affect CR rates. A more common use of growth factors, both in clinical trials and in standard practice, has been in the post-chemotherapy stage of treatment. There is generally a two- to three-week delay in the recovery of neutrophil number following the completion of chemotherapy, and elderly patients in particular are at high risk for severe infection and early death. One complicating factor has been the theoretical concern that growth-factor use would stimulate residual leukemia cells to proliferate, thus limiting the effectiveness of induction therapy. Preclinical studies have supported this theory with the fi nding that G-CSF and GM-CSF can upregulate procaspase protein levels in leukemia cell lines, further pro- moting cell survival and proliferation [74]. Several groups have investigated the use of growth factors on various days following the completion of chemo- therapy, and there has been no evidence of inferior clinical outcome [25,60,67,75,76]. With the use of G-CSF or GM-CSF following induction, there have been reports of a two- to six-day improvement in neutrophil recovery time. In some studies, this has resulted in fewer hospitalization days and reduced incidence of severe infections. However, only one study to date has reported an improved overall sur- vival with the use of GM-CSF [76]. Given the current evidence, the use of growth-factor support after induction chemotherapy is unlikely to be harm- ful and may reduce the number of days the patient remains neutropenic and thus susceptible to severe infections. Multi-drug resistance gene Leukemia cells that overexpress Pgp have clearly been shown via in-vitro model systems to demon- strate resistance to cytotoxic chemotherapy [48]. The ability to effectively block Pgp export of anthra- cyclines might be of considerable benefi t to elderly AML patients, who frequently express this pheno- type [27]. SWOG conducted a trial using placebo vs. cyclosporine A (CsA), a potent competitive Pgp inhibitor, in conjunction with sequentional cytara- bine and infusional daunorubicin [49]. The results from over 200 adult AML patients indicated that there was a signifi cant reduction in the amount of resistant disease in the patients who received CsA with chemotherapy in comparison to placebo (31% vs. 47%). Although there was no difference in CR rate between the two arms, CsA-treated patients had modestly improved DFS and OS. Unfortunately, other trials utilizing Pgp inhibitors have not yielded positive results [50,77,78], so this strategy remains investigational. However, because of the high preva- lence of the MDR1 phenotype in the elderly popu- lation, there is continued investigation into the use of more potent and specifi c inhibitors of Pgp function. Consolidation The majority of older adult patients with AML will experience relapse of their disease, with only 0–20% of elderly patients achieving long-term survival (Fig. 19.2) [24]. Given this dismal prognosis, attempts to reduce the risk of relapse with consolidation chemo- therapy, maintenance therapy, and transplant have been explored. Younger patients with good or inter- mediate prognosis have shown clear benefi t with one to four cycles of high-dose cytarabine, although the optimal number of cycles has not yet been defi ned [56]. Unfortunately, no standard consolida- tion regimen has been identifi ed in elderly patients, owing in part to the resistant nature of their disease and also to relative intolerance of high-dose chemo- therapy. The majority of studies have utilized one or two courses of the same regimen that was used in induction, or an intermediate dose of cytarab- ine, with resultant long-term survival rates in the range of 10–15% [61,62,68,75]. There has been no clear evidence to date that a more prolonged con- solidation phase will improve clinical outcome. Acute myeloid leukemia 245 In the MRC AML11 trial, elderly patients were ran- domized to shorter (3) or longer (6) courses of com- bination chemotherapy as consolidation [25]. No improvements were seen with respect to DFS or OS in patients treated on the longer chemotherapy regimen. Furthermore, there have been no ran- domized studies indicating that there is a benefi t of additional chemotherapy beyond cytarabine alone. When single-agent cytarabine (100 mg/m 2 CIVI for 7 days) was compared to cytarabine (500 mg/m 2 every 12 hours for 6 doses) and mitoxantrone (5 mg/ m 2 every 12 hours for 6 doses) in elderly AML patients in complete remission, there was no improvement with respect to leukemic relapse or overall survival with the addition of anthracycline [79]. The optimal regimen of consolidation cytarabine for adult patients with AML was investigated by the Cancer and Leukemia Group B (CALGB). Over 1000 patients received standard induction chemotherapy with daunorubicin and cytarabine, and were ran- domized upon confi rmation of remission to one of three chemotherapy arms: cytarabine 100 mg/m 2 CIVI for 5 days (low dose) vs. cytarabine 400 mg/m 2 CIVI for 5 days (intermediate dose) vs. cytarabine 3 g/m 2 given every 12 hours on days 1, 3, and 5 (high dose) [56]. For patients younger than 60, DFS was superior in the high-dose arm. However, in the eld- erly patients, there was no signifi cant difference between arms. This fi nding was related in part to the poor tolerability of the high-dose cytarabine in the elderly cohort, with the main adverse event being neurotoxicity. As a result, high-dose cytarabine can- not be routinely recommended as consolidation therapy for patients older than 60. Strategies utiliz- ing an intermediate dose of cytarabine have shown acceptable tolerability, but still with disappoint- ingly low DFS rates [62,81]. Thus there is no estab- lished standard consolidation regimen for elderly patients. Post-remission therapy must be tailored to the individual patient, taking into consideration associated comorbidities and demonstrated toler- ance to induction chemotherapy. One to two cycles of intermediate-dose cytarabine or repeated cycles of combination chemotherapy represent reasonable options. Maintenance chemotherapy Over the last few decades, various maintenance therapies have been investigated as post-remission therapy in elderly patients with AML. Interferon, interleukin 2 (IL-2), low-dose cytarabine, and combination chemotherapy are some of the treat- ments that have been administered for various lengths of time post-consolidation [25,56,60,62,82]. Unfortunately, in studies that have compared Figure 19.2 Patients Ͼ55 years with newly diagnosed AML treated on Eastern Cooperative Oncology Group (ECOG) protocols since 1973. From Appelbaum et al., Hematology Am Soc Hematol Educ Program 2001; 62–86 [80]. 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 Years Study Year: 1989–1997, n ϭ 553, Median Survival ϭ 8.2 Months, 5-Year Survival ϭ 12% Study Year: 1983–1986, n ϭ 142, Median Survival ϭ 6.3 Months, 5-Year Survival ϭ 13% Study Year: 1973–1979, n ϭ 293, Median Survival ϭ 3.5 Months, 5-Year Survival ϭ 6% Survival 246 Magda Melchert, Jeffrey Lancet maintenance therapy to placebo in the elderly, they have been unsuccessful in reducing the risk of relapse or improving OS [25,60]. It is clear that post- remission therapy in elderly patients needs to be optimized, as the majority of those that achieve CR will ultimately relapse. Transplant Older adults are under-represented in transplanta- tion trials in AML, making it diffi cult to predict sur- vival and treatment-related mortality (TRM) rates. Historically, patients older than 55 or 60 were not considered to be eligible for transplant, because of concerns of early death or debilitating morbidity. However, there have been substantial changes in transplantation protocols over the last decade, with the use of more tolerable conditioning regimens, substitution of peripheral-blood progenitor cells (PBPC) for bone-marrow cells in transplant, and improved supportive care measures. Autologous transplant in the elderly has been studied in a small feasibility study including 19 patients between the ages of 60 and 70 after induc- tion chemotherapy and one cycle of consolidation [83]. While only two toxic deaths were reported as a result of transplantation, 14 of the 19 patients expe- rienced early relapse following autologous trans- plant. Conversely, a large retrospective review of 193 patients between the ages of 60 and 75 who under- went autologous transplantation between 1984 and 1998 in fi rst complete remission (CR1) did demon- strate a 47% three-year overall survival, suggest- ing a possible benefi t to aggressive post-remission therapy [84]. However, TRM was signifi cant at 15%. The European Bone Marrow Transplant group published a similar experience in 111 patients between the ages of 50 and 60 who underwent allo- grafting in CR1 [85]. The four-year leukemia-free survival was also promising at 34%, but the TRM remained substantial at 28%. Hence it appears that while autografting for AML in older adults poten- tially promotes extended survival, severe regimen- related toxicity remains a barrier to optimal outcomes. While outcomes have been generally poor for ablative allogeneic transplants in the elderly [86], somewhat more promising outcomes may be seen with non-myeloablative and reduced-intensity allo- geneic regimens [87–89]. Reduced-intensity strate- gies have been employed to take advantage of the T-cell-mediated graft versus leukemia (GVL) effect without the added toxicity of high-dose chemother- apy. In a small study of 19 elderly patients with active leukemia, reduced-intensity conditioning regimen followed by allogeneic stem-cell transplant resulted in an overall one-year survival of 68% and one-year non-relapse mortality of 22% [88]. Non-myeloabla- tive regimens have produced similarly promising outcomes, with relatively low TRM and favorable one-year survival rates [87,90]. However, reduced- intensity and non-myeloablative regimens have signifi cant relapse rates. Larger, prospective multi- center trials are needed to further elucidate the benefi t of allogeneic transplant in the elderly [91]. While transplant cannot be routinely recommended for elderly patients with AML, further investigation of reduced-intensity allogeneic regimens or autolo- gous transplant is warranted. Salvage chemotherapy The majority of elderly patients with AML who achieve CR will eventually relapse, and salvage therapy thus becomes an option for many of these patients. Unfortunately, response rates with subse- quent chemotherapy drop precipitously, with the remission rates in most studies ranging from 10% to 80% [92–94]. The large variability in response is essentially due to various prognostic factors, such as the length of fi rst remission and cytogenetics. The most important predictor of response to salvage therapy is the length of the patient’s CR1. For remis- sions lasting at least one year, CR rates of 40–60% can be expected, in contrast to a 10–20% CR rate for those patients who have refractory disease or shorter remission durations [92,93,95,96]. Because of the unfavorable outcomes, salvage chemother- apy is often used as a bridge to allogeneic transplant Acute myeloid leukemia 247 once a second or third CR is achieved. This is usually not a viable option for the vast majority of patients over the age of 60. There is, however, a small portion of patients (approximately 10–15%) who can survive long term following a second remission induction, thus making salvage therapy alone a reasonable option for elderly patients [93]. Multiple chemo- therapy regimens have been used in this setting, but there is no clear optimal choice for second-line treatment. Cytarabine-based regimens remain the most commonly administered of the salvage proto- cols. For patients with an initial remission dura- tion greater than one year, cytarabine alone or in combination with other drugs can signifi cantly improve OS when compared to those who received investigational agents [93]. The same is not true for patients with short CR1 or refractory disease. The addition of an anthracycline to high-dose cytara- bine can improve rates of second CR and length of disease-free survival, especially in patients who exhibit resistance to cytarabine alone [97]. When etoposide is used concurrently with cytarabine and an anthracycline (idarubicin) as salvage therapy in refractory/relapsed AML, comparable remission rates are seen (40%) with reasonable toxicity profi les [98]. A randomized phase III trial that explored the benefi t of adding etoposide to high-dose cytarabine did reveal an improvement in remission duration (11.9 months vs. 25 months); however, there was no difference in OS, and the effect was diminished in patients over the age of 50 [99]. The combination of mitoxantrone, etoposide, and cytarabine is a com- monly used treatment strategy, generally producing CR rates of 40–80% with a favorable toxicity profi le [94,100]. The addition of purine analogs to cytarab- ine has also produced promising results in relapsed or refractory patients. Cytarabine and G-CSF with 2-chlorodeoxyadenosine (2-CdA), or the CLAG regi- men, has produced CR rates of approximately 50% for patients initially unsuccessful with standard induction therapy [101,102]. The FLAG regimen, which is composed of fl udarabine, cytarabine, and G-CSF, similarly has resulted in CR rates of 50–70% for the treatment of AML and high-risk MDS in the fi rst-line setting [103,104]. Fludarabine with cytara- bine in the relapsed/refractory setting has a reported CR rate of 36% [105]. Non-cytarabine regimens have also been inves- tigated in the salvage setting. This is of particular interest to the elderly population, given the higher incidence of neurotoxicity associated with this drug in patients over age 60. For example, continuous infusion of carboplatin has modest activity as sal- vage therapy in AML, with complete response rates of 7–16% being reported [106]. The only new agent to gain FDA approval in the past several years for the treatment of AML is gemtuzumab ozogamicin (GO; Mylotarg). GO is a humanized monoclonal antibody directed against CD33, which is present on myeloid blast cells in over 80% of patients with AML, and is conjugated to an anti-tumor antibiotic, calicheamicin. Approved for the treatment of older adults with AML in fi rst relapse, this drug has a reported CR rate of 26%, but carries the risks of prolonged myelosuppression and hepatic veno-occlusive disease [107]. Novel therapies Acute leukemia in the elderly has a distinct disease biology, more commonly arising from myelodys- plasia or secondary to cytotoxic chemotherapy. As a result, cytogenetic and other molecular abnormali- ties are frequently associated, leading to an inher- ent resistance to our standard drugs. As specifi c molecular abnormalities are identifi ed in leuke- mic blast cells, i.e., FLT3-ITD, Ras proto-oncogene, and MDR1, novel therapies are developed to target these abnormalities. For example, multiple small- molecule tyrosine kinase inhibitors of FLT3 are currently under investigation. Phase I and II trials with agents such as CEP-70, PKC, and SU11248 have shown promise, with hematologic and bone-mar- row responses in patients with refractory or recur- rent AML and documented activating mutations [108–110]. These drugs are generally well tolerated, and may eventually prove to be especially useful in AML, when combined with standard chemothera- peutic agents. [...]... L-asparaginase and vincristine from the treatment protocols But the long-term survival continues to be lower (40–55%) than in the pediatric population, whether single-institution or cooperative group studies are analyzed (Table 20.5) Achieving a CR with induction therapy is a sine qua non for a long-term survival in adult ALL, with only 5% OS in those patients not achieving a CR with the initial therapy... ABL tyrosine kinase, which is implicated in the pathogenesis of Phϩ leukemias Imatinib, a selective inhibitor of the abnormal tyrosine kinase, has demonstrated substantial activity against CML, but also in acute leukemias characterized by the BCR-ABL fusion protein [61 ] The role of imatinib as salvage therapy, as well as the addition of imatinib to standard chemotherapy during induction and during consolidation... an age-adapted design, with generally less aggressive chemotherapy in the elderly [44,49–53] Indeed, a number of non-randomized sequential trials have found age-adapted therapy to be superior to young-adult-like therapy in terms of CR rate ( 96% vs 60 %) However, no significant benefit in DFS or OS was noted [7] Others have reported a standard chemotherapy induction regimen (daunorubicin, vincristine, prednisone,... between the three groups in terms of DFS [55] Monoclonal antibodies ALL cells express a number of well-characterized antigens in their cell surface which could be the target of monoclonal antibodies Preliminary reports in refractory patients indicate that rituximab (antiCD20), gentuzumab ozogamicin (anti-CD33), and alemtuzumab (anti-CD52) have in- vitro and in- vivo anti-tumor activity against ALL [ 56 60 ] These... short induction regimen with high doses of cytarabine 3 g/m2 per day for five days and mitoxantrone 80 mg/m2 as a single course, producing a CR rate of 84% in a seemingly shorter time than in the previous standard regimen experience at the Sloan-Kettering Institute [45] Furthermore, in an expanded randomized study including 161 ALL patients, the cytarabine/mitoxantrone combination appeared superior to the. .. leukemia in the elderly: characteristics and 269 270 Salvador Bruno, Fermina Mazzella, Oscar Ballester 52 53 54 55 56 57 58 59 60 61 62 outcome with the vincristine-adriamycin-dexamethasone (VAD) regimen Br J Haematol 1994; 88: 94–100 Spath-Schalbe E, Heil G, Heimpel H Acute lymphoblastic leukemia in patients over 59 years of age: experience in a single center over a 10-year period Ann Hematol 1994; 69 :... anthracycline-based regimen, CR and OS rates were not significantly different from those achieved by the under-75 age group, and they are also comparable to those obtained in previous studies of intensive chemotherapy in an elderly population over the age of 60 years [23,55 ,61 ,62 ,73,123] Nonetheless, treatment-related mortality remains high for elderly patients, and as patients become older than 70 they... Final Report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organization for the Research and Treatment of Cancer (EORTC-LCG) and the Dutch Belgian Hemato-Oncology Cooperative Group (HOVON) Blood 1997; 90: 2952 61 61 Anderson JE, Kopecky KJ, Willman CL, et al Outcome after induction chemotherapy for older patients with Acute myeloid leukemia 62 63 64 65 66 67 68 ... pre-B ALL, 5% B-ALL (Burkitt), and 1–2% are early B-precursor ALL Approximately 20% have a T-cell phenotype In the older adult population, pre-B and common B-ALL are most frequently encountered, while T-cell ALL is under-represented when compared to the younger age groups Interestingly, T-cell ALLs also show age-related differences in phenotype, with a shift from predominantly TCR-expressing type in. .. chemokines that alter the bone-marrow microenvironment, in uence angiogenesis, and support the proliferation of this abnormal cell population Among the more well-described chemokines that are involved in the pathophysiology of multiple myeloma are tumor necrosis factor α, interleukin 6 (IL -6 ) , interleukin 1β, receptor activator of nuclear factor κB ligand (RANKL), and macrophage in ammatory protein 1α . remains investigational. However, because of the high preva- lence of the MDR1 phenotype in the elderly popu- lation, there is continued investigation into the use of more potent and specifi c inhibitors. have been investigated as post-remission therapy in elderly patients with AML. Interferon, interleukin 2 (IL-2), low-dose cytarabine, and combination chemotherapy are some of the treat- ments. for the treatment of AML and high-risk MDS in the fi rst-line setting [103,104]. Fludarabine with cytara- bine in the relapsed/refractory setting has a reported CR rate of 36% [105]. Non-cytarabine