Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia

Leukemia Research 47 (2016) 149–160

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Leukemia Research journal homepage: www.elsevier.com/locate/leukres

Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia Jonathan Kell University Hospital of Wales, Department of Haematology, Heath Park, Cardiff, GB, United Kingdom

a r t i c l e

i n f o

Article history: Received 25 May 2016 Accepted 30 May 2016 Available online 11 June 2016 Keywords: Acute myeloid leukemia Relapse Refractory

a b s t r a c t Despite advances in understanding the complexities of acute myeloid leukaemia (AML), the treatment of refractory or relapsed AML (rrAML) remains a daunting clinical challenge. Numerous clinical trials have failed to identify new treatments or combinations of existing therapies that substantially improve outcomes and survival. This may be due, at least in part, to heterogeneity among study patients with respect to multiple inter-related factors that have been shown to affect treatment outcomes for patients with rrAML; such factors include age, cytogenetics, immunophenotypic changes, and (in the case of relapsed AML) duration of first complete remission, or if the patient has had a previous blood and marrow transplant (BMT). A clear understanding of disease characteristics and patient-related factors that influence treatment response, as well as expected outcomes with existing and emerging therapies, can aid clinicians in helping their patients navigate through this complex disease state. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Impact of patient characteristics on outcomes in relapsed/refractory acute myeloid leukaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 2.1. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 2.2. Duration of first complete remission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 2.3. Cytogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 2.4. Molecular abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 2.5. Immunophenotypic changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Current chemotherapy for relapsed/refractory acute myeloid leukaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 3.1. Non-intensive regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 3.2. Intensive regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 3.3. Haematopoietic cell transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 3.4. Current clinical approach and unmet needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 Phase 3/late-stage investigational chemotherapy in rrAML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 4.1. Laromustine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 4.2. Clofarabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 4.3. Elacytarabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 4.4. Vosaroxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

1. Introduction

E-mail address: [email protected] http://dx.doi.org/10.1016/j.leukres.2016.05.025 0145-2126/© 2016 Elsevier Ltd. All rights reserved.

Acute myeloid leukaemia (AML) is the most common of the acute leukaemias among adults [1], with approximately 20,000 new cases expected in the US in 2015 [2] and an estimated incidence of 18,000 new cases annually in the European Union [3]. AML

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is primarily a disease of older adults; the median age at diagnosis is approximately 67 years [2]. Although survival has generally improved since the 1980s and 1990s, the 5-year relative survival rate still is only about 25% in the US [2] and is 15% to 20% in Europe [3–7]. Induction therapy with intensive chemotherapy regimens can produce a complete remission (CR) in about 50% to ≥80% of adult patients with newly diagnosed AML [8,9]. However, this leaves many patients who do not respond to induction treatment. Also, even among patients who achieve CR, the majority eventually relapse despite receiving post-remission therapy; relapses can occur several months to years after the initial remission, but the risk is highest within the first 3 years after initial treatment [10–12]. Thus, refractory or relapsed AML (rrAML) is a relatively common clinical scenario, but one that is difficult to manage, as effective therapies are limited. Also, rrAML is a very heterogeneous disease in which patient and disease characteristics need to be carefully considered when managing treatment over time. Overall, patients with rrAML have a poor prognosis and few treatment options, as there currently is no standard of care [8,13]. Challenges in treating patients with rrAML include accurately assessing the disease prognosis and likelihood of achieving CR, selecting the salvage therapy that is most likely to succeed and that can be tolerated, and identifying patients for whom haematopoietic cell transplantation (HCT) is a viable option [14]. The purpose of this manuscript is to discuss the clinical considerations that present challenges in trying to achieve effective treatment of rrAML. In the context of these considerations, current treatment guidelines and emerging treatment options for rrAML in late-stage development are also reviewed. References for this review were identified through searches of PubMed with the search terms “(‘acute myeloid leukemia’ OR “acute myeloid leukaemia” OR “acute myelogenous leukemia” OR “acute myelogenous leukaemia”) AND (relaps*[ti] OR refractory [ti]) NOT child*” and were limited to those published in the last 10 years. Articles were also identified through reviews of reference lists from the retrieved articles and treatment guidelines. Only papers published in English were reviewed. The final reference list was generated on the basis of relevance to the scope of this review. 2. Impact of patient characteristics on outcomes in relapsed/refractory acute myeloid leukaemia Several patient characteristics are relevant in assessing a patient’s prognosis and in selecting appropriate treatments for rrAML. Multiple inter-related factors, including age, cytogenetics, immunophenotypic changes, and (in the case of relapsed AML) duration of first CR, have been shown to affect treatment outcomes for patients with rrAML [15–18]. Variability in these characteristics among patient populations in treatment studies may be one reason why clinical trials thus far have failed to identify a single preferred regimen or standard of care [13]. 2.1. Age Age is an important prognostic factor in patients with rrAML, with younger patients generally having a better prognosis than older patients. In AML in general, epidemiological data have shown that survival decreases as age increases, particularly in patients aged ≥65 years [5,6,19]. Considering rrAML specifically, age has been identified as one of several significant predictors of both response to salvage treatment [20] and survival [15,17,20]. For example, the prognostic index for patients aged 15–60 years in first relapse, developed by Breems and colleagues, includes age at relapse (3 strata: ≤35 years, 36–45 years, and >45 years); younger

age at relapse was associated with improved survival [15]. Similarly, retrospective analysis by Kurosawa and colleagues found that among patients aged 16–70 years in first relapse, overall survival (OS) was significantly longer for the subgroup of patients aged ≤49 years compared with the subgroup aged ≥50 years (P < 0.001); however, age was not identified as an independent prognostic factor in a multivariate analysis [17]. Several characteristics of AML may vary with age and contribute to poor treatment response or survival in older patients. Analysis of several studies by the Southwest Oncology Group (SWOG) found that likelihood of unfavourable cytogenetics increased with age, especially for those >75 years old; the rate of unfavourable cytogenetics was 35% among patients aged <56 years compared with 50% in those aged >75 years, while the incidence rates of favourable cytogenetics were 17% and 4%, respectively (P < 0.001 [test for heterogeneity among age groups]) [21]. This study showed that older patients more commonly have AML that expresses multidrug resistance (33% of patients aged <56 years versus 61% to 62% among patients aged 56–75 years, and 57% of patients aged >75 years) and that is resistant to chemotherapy (27% of patients aged <56 years and 36% among those aged >75 years) [21]. Although not specific to refractory or relapsed disease, these characteristics contribute to the challenge in finding effective treatments that can produce CR and improve survival in patients with rrAML, particularly those who are older. In addition to considerations regarding efficacy, treatment selection for patients with rrAML also must take into consideration age and age-related factors that may affect the intensity of treatment that the patient may be able to tolerate. Treatment guidelines for rrAML (and for newly diagnosed AML) generally use a threshold of 60 years as a therapeutic divergence point and include lowerintensity treatment options for older patients, particularly those older than 75 years and/or who are unlikely to tolerate standard treatment [1,8,22]. However, treatment decisions should not be based on age alone; rather, disease characteristics (e.g., cytogenetic risk) and other relevant patient characteristics should be taken into account [1,8,22]. Age-related factors also can have an impact on the tolerability or toxicity of treatment for older patients with rrAML. For example, older patients have an increased likelihood of the following: comorbid conditions, along with concomitant medications that could contribute to drug-drug interactions; impaired renal or liver function that could decrease drug clearance; reduced immune competence; and poor performance status, particularly following intensive initial treatment [23]. Performance status, creatinine, and albumin were among the variables included in multivariate models for predicting early mortality (at 28, 60, or 90 days) in patients with rrAML recently described by Godwin and colleagues [24]. 2.2. Duration of first complete remission For patients with relapsed AML, duration of first CR (CR1) is widely recognised as an important predictor of outcome after salvage therapy; longer duration of CR1 is associated with better survival [15,17,18,25]. CR rate and disease-free survival (DFS) following salvage therapy decrease continuously as duration of CR1 decreases [26]. In the European Prognostic Index (EPI), risk based on duration of CR1 is stratified into 3 categories: ≤6 months, 7–18 months, or >18 months [15]. A threshold of 12 months is used in some treatment guidelines and prognostic indexes [1,18], as it has been shown that patients whose CR1 lasts longer than 12 months generally have a better prognosis (higher second CR [CR2] rates and longer survival) [20]. In particular, CR1 less than 6 months has been associated with poor survival following salvage therapy (e.g., intensive chemotherapy, HCT, or other treatments) [15,27]. Recent analysis of data from the HOVON/SAKK

J. Kell / Leukemia Research 47 (2016) 149–160

and SWOG S0106 trials found that survival after treatment failure was similar for patients with CR1 ≤6 months and those with primary refractory AML [28], suggesting patients with very short CR1 may not truly have reached a molecular or functional CR. Duration of CR1 also can help to inform treatment selection. A longer CR1 suggests that the leukaemic blasts are likely to be more sensitive to the initial induction chemotherapy (typically cytarabine/anthracycline-based regimens), and as such, the same or a similar regimen may be effective as salvage therapy [1,13]. 2.3. Cytogenetics In patients with AML, cytogenetic karyotype is the single most important factor after age for predicting remission rate, relapse risks, and OS outcomes [1,8,18,29,30]. Cytogenetic risk status is typically categorised as favourable, intermediate, or adverse/unfavourable/poor. Specific classification systems may vary, but generally favourable risk includes core binding factor (CBF) AML—i.e., AML with inv(16) or t(16;16) or t(8;21); intermediate risk includes normal cytogenetics and trisomy 8; and unfavourable risk includes complex karyotype (≥3 clonal chromosomal abnormalities) and monosomal karyotype (≥2 autosomal monosomies, or a single monosomy with additional structural abnormalities), the latter of which is a subgroup of the unfavourable risk category that is associated with very poor prognosis [1,8,22]. These risk categories are relevant for assessing prognosis, not only in newly diagnosed patients [29,30], but also in those with rrAML [17,31]. Unfavourable cytogenetics predict lower likelihood of achieving CR and shorter OS [17,31]. As such, cytogenetic risk status is included as a factor in prognostic scoring systems for patients with rrAML [15,18]. Given that patients with poor- or intermediate-risk cytogenetics at diagnosis are less likely to achieve CR and more likely to experience relapse if they do achieve CR [32], it is not surprising that the majority of patients with rrAML do not have favourable cytogenetics [18,31]. This is particularly evident in older patients; in one study of older patients with AML in first relapse, only 4% had favourable cytogenetics [33]. Again, this is not surprising, as the incidence of adverse cytogenetics also increases with age [21]. Poor cytogenetic risk may be particularly common in patients with refractory AML. In one study of patients with refractory (n = 22) or relapsed (n = 25) AML, more than half (59%) of patients with refractory AML had a poor-risk karyotype compared with 12% of patients with relapsed AML (P = 0.02) [16]. An additional potential complicating factor is the occurrence of karyotype changes between first diagnosis and relapse, as karyotype at relapse may be a stronger predictor of outcomes than karyotype at diagnosis [34]. Changes in karyotype have been shown to occur more frequently among patients with unfavourable cytogenetics at diagnosis and (regardless of the specific changes) may be associated with a shorter time to relapse and increased resistance or refractoriness to treatment [34]. A retrospective study (n = 58) found that patients with karyotype changes had a lower response rate with salvage therapy, as well as shorter overall and event-free survival (EFS) [35]. 2.4. Molecular abnormalities In addition to cytogenetics, molecular abnormalities can serve as prognostic indicators, particularly in patients with cytogenetically normal AML; molecular markers are included in risk stratification systems outlined in treatment guidelines [1,8]. Internal tandem duplication (ITD) of the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), present in about 20%–30% of adult patients with AML, has been associated with poor prognosis [36,37]. For example, in a study of patients with newly diagnosed AML, FLT3-ITD was

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associated with shortened relapse-free survival and OS [38]. Similarly, studies of patients with relapsed AML have shown that FLT3-ITD is a significant negative predictor of survival following relapse [18,39,40]. Mutation of the nucleophosmin 1 (NPM1) gene, found in around 30% of AML, has been associated with better clinical outcomes (higher CR rates and longer DFS and OS) in patients with newly diagnosed AML, particularly in the absence of FLT3ITD [41]. However, in patients with relapsed AML, NPM1 status was not consistently a significant predictor of CR2 or OS [18,40,42]. Alterations of the tumour suppressor gene TP53, which have been reported in about 10% to 15% of AML patients, are strongly associated with cytogenetic aberrations (frequencies up to about 80% have been reported among patients with complex karyotype) and poor outcomes [43–46]. A study of patients with AML with complex karyotype found that, compared with patients without TP53 alterations (n = 62), patients with TP53 alterations (n = 157) were older (median age: 61 vs 54 years; P = 0.002), were more likely to have monosomal karyotype (87% vs 55%; P < 0.0001), had lower CR rates following induction therapy (28% vs 50%; P = 0.01), and had reduced survival (median OS: 4.14 months vs 10.97 months; P < 0.0001) [44]. Mutations of other genes, including CEBPA, WT1, IDH1, and IDH2, have not been shown to significantly affect prognosis in rrAML [40], although data are limited. Recently, a small study (n = 20) found that expression levels of CD44 and of phosphatase and tensin homolog (PTEN) may have prognostic value in elderly patients with refractory AML; specifically, positive CD44 expression was significantly correlated with poor OS (hazard ratio [HR]: 6.281 [95% CI, 1.78–22.12; P = 0.0042]), negative PTEN expression was associated with a tendency toward reduced survival (HR: 2.689 [95% CI, 0.89–8.08; P = 0.078]), and patients who were both CD44 negative and PTEN positive had significantly increased survival compared with those who were CD44 positive and PTEN negative (HR: 0.037 [95% CI, 0.006–0.222; P = 0.0006]) [47]. Molecular abnormalities may ultimately play a role in treatment selection; a number of targeted therapies are currently in development [48]. 2.5. Immunophenotypic changes Detection of leukaemia-associated aberrant immunophenotypes (LAIPs) is used in assessing minimum residual disease, which plays a role in prognosis and management of AML [16,49]. Similar to changes in karyotype, changes in LAIP may occur between initial diagnosis of AML and first relapse or refractory/persistent disease [49]. In a study of 47 patients with rrAML, the majority of patients (76% of those with refractory disease and 84% of those with relapse) had changes in LAIPs [16]. However, only 14% and 44% of refractory and relapsed patients, respectively, showed cytogenetic clonal evolution, suggesting that while cytogenetic clonal shifts may contribute to changes in LAIPs, there may also be an effect of treatment that leads to development of persistent disease or relapse [16]. 3. Current chemotherapy for relapsed/refractory acute myeloid leukaemia Treatment guidelines recommend enrolment in clinical trials for all patients with AML [1,8,22,50]; in particular, NCCN recommendations indicate that a clinical trial is the strongly preferred option for all patients with rrAML [1]. For each patient, the most appropriate course of treatment will depend on whether treatment with a curative intent is realistically possible (considering the factors discussed above) and whether the patient can tolerate such treatment (based on such factors as age, performance status, comorbidities, and prior treatment), as well as whether the patient wishes to undergo such treatment [1,8,22,50]. While HCT may be the goal

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of therapy for some patients (e.g., younger or healthier patients), best supportive care or palliative treatment (which may incorporate transfusion support or hydroxycarbamide, for example) may be the most appropriate choice for some patients [1,8,22,50]. Salvage chemotherapy for rrAML is generally aimed at inducing CR, which can be followed by consolidation with HCT [8]. As previously noted, patients in relapse who had a long duration of CR1 may respond to re-induction with the same regimen that was used for initial induction [1]. Table 1 [1,8,9,48,51,52] provides an overview of the agents included and Table 2 [51–64] summarises selected studies of various salvage regimens included in treatment guidelines [1,8,22]. 3.1. Non-intensive regimens Non-intensive treatment options include low-dose cytarabine or hypomethylating agents (azacitidine or decitabine), which may be considered for patients unable to tolerate more intense regimens [1]. The combination of hypomethylating agents with the kinase inhibitor sorafenib now provides another option for patients with FLT3-ITD mutations [1]. CR rates with non-intensive regimens generally range from about 10% to 20%, although one small study reported rates of 38% and 50% for patients with refractory and relapsed disease, respectively [33,52–56,65]. Effects of various factors discussed earlier can be seen in studies of non-intensive regimens. For example, in one study of azacitidine (n = 130), median OS was shorter among patients with high-risk cytogenetics (6.0 months) compared with those with intermediate-risk karyotype (9.5 months; P = 0.002), and highrisk cytogenetics was an independent negative prognostic factor (HR = 1.68 [1.08–2.61], P = 0.022) [56]. In another study with azacitidine (n = 47), relapse at >12 months was a significant predictor of CR in a univariate analysis (OR 8.46, CI: 1.78–40.36; P = 0.0046), and was retained as an independent prognostic factor based on multivariate analysis; median survival was also longer in patients with late relapse compared with those with early relapse or refractory AML, although the difference was not statistically significant (11 months vs 7.4 months, respectively; P = 0.19) [54]. Relapse postazacitidine remains a potentially significant problem [66]. 3.2. Intensive regimens Regimens for intensive salvage chemotherapy typically include cytarabine [22], although high-dose cytarabine (HiDAC) may not be appropriate for patients who had received it previously [1] or for older patients (e.g., over age 60 years) due to a high risk of toxicity [8]. Cytarabine-based regimens include HiDAC (2–3 g/m2 ) alone or in combination with an anthracycline (eg, daunorubicin or idarubicin) and have been used for the past 3 decades. Over time, additional cytarabine-based regimens evolved, including HiDAC or intermediate-dose (1 g/m2 ) cytarabine in combination with cladribine or fludarabine, mitoxantrone, idarubicin, and/or etoposide [1,8,22]. Overall CR rates with intensive regimens generally range from about 30% to about 65%, and median OS is generally around 8–9 months (see Table 2) [51,57,60–64]. Rates of early death (e.g., induction deaths, aplastic deaths or 30-day mortality) in these studies were generally between about 5% and 15% [51,57,60–64]. A combination of mitoxantrone and etoposide is another option, which is associated with similar CR rates and OS around 6 months [58,59]. Studies of these regimens illustrate how the various factors previously discussed can have an impact on CR rates and survival. For example, in a study of patients with rrAML who received fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF; n = 38), karyotype was significantly related to response, with a CR rate of 75% among patients with a normal karyotype

compared with 25% of those with an aberrant karyotype (P = 0.02) [61]. In patients with rrAML treated with cladribine, cytarabine, GCSF, and mitoxantrone (n = 114), multivariate analysis showed that age (≥34 years) and poor karyotype were significantly associated with decreased probability of OS, and poor karyotype was associated with decreased probability of DFS [62]. In a study of patients with rrAML (n = 32) treated with etoposide, cytarabine, and mitoxantrone, age significantly affected CR rate (76% in patients <50 years vs 29% in patients ≥50 years; P = 0.03); remission rates were higher in early relapsed (87%) vs refractory (56%) AML, although that difference was not significant (P = 0.28) [60]. In relapsed patients treated with clofarabine, cytarabine, and G-CSF (n = 50), multivariate analysis showed significantly reduced CR rates and higher mortality for patients whose CR1 lasted less than 38 weeks [64]. 3.3. Haematopoietic cell transplantation HCT is often the best option for cure or long-term remission of AML. In patients with rrAML, HCT may be given following salvage chemotherapy or as salvage treatment. Overall, outcomes for patients with relapsed AML are better if HCT is performed when a patient is in CR2 rather than in patients with active or more advanced disease [67–69]; however, even for patients who receive HCT in CR2, disease-free (or leukaemia-free) survival remains poor (around 30% at 5 years) [68,69], with 5-year OS rates of approximately 35%–40% [69,70]. In refractory patients, HCT generally has had limited success and is associated with considerable non-relapse morbidity and mortality [8,50,68]. However, as with chemotherapy, patient- and disease-related factors can influence outcomes. A study of HCT in patients with primary induction failure or relapse (n = 2255, including 1673 patients with AML) identified 5 negative predictor variables (CR1 duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics) and found that survival for low-risk patients was nearly comparable to that of patients who received HCT in CR; although the overall 3-year survival rate for patients with AML was 19%, the rate was 42% for those with the lowest risk compared with 6% among those with the highest risk [27]. Therefore, HCT may be an option to consider for selected patients with rrAML who are not in remission. Alternative conditioning regimens (reduced intensity conditioning) may help to address non-relapse mortality [71]. 3.4. Current clinical approach and unmet needs Fig. 1 outlines a clinical approach to treating patients with rrAML, incorporating current treatment strategies. Determining a patient’s fitness for intensive treatment is a key consideration and takes into account factors discussed earlier, such as age, comorbidities, and previous treatments. Standard treatment options in clinical practice include low-dose cytarabine or supportive care (e.g., oral hydroxycarbamide) for patients not fit for intensive therapy and HiDAC or FlaG-Ida as intensive treatments. Some investigational agents may be available on a compassionate-use basis; these agents, usually administered in combination with HiDAC, may be considered for certain patients. Overall, current salvage chemotherapy options for rrAML offer moderate to poor CR2 rates and OS. Both initial induction/consolidation and salvage treatments can have high rates of adverse reactions and toxicity that lower performance status, which may limit patients’ options for subsequent treatment for refractory disease or relapse, including HCT. Even for patients who are candidates for intensive salvage treatment, the substantial risk of non-relapse mortality/treatment-related mortality associated with these regimens must be considered alongside the potential response and survival benefits. Treatment decisions for elderly

Table 1 Overview of current chemotherapy agents for relapsed/refractory acute myeloid leukaemia. Nucleoside Analogues Agent

Cytarabine

Fludarabine

Cladribine

Drug category

Deoxycytidine analogue [48]

Purine analogue/ribonucleotide reductase (RNR) inhibitor [48]

Purine analogue/ribonucleotide reductase (RNR) inhibitor [48]

Other intensive agents Agent

Doxorubicin

Daunorubicin

Idarubicin

Mitoxantrone

Etoposide

Drug category

Anthracycline [51]

Anthracycline [9]

Anthracycline [9]

Anthracenedione [8]

Topoisomerase inhibitor [1]

Non-intensive Agents Agent

Azacitidine

Decitabine

Sorafenib

Hypomethylating agent [48]

Hypomethylating agent [48]

FLT3 tyrosine kinase inhibitor [52]

Structurea,b,c

J. Kell / Leukemia Research 47 (2016) 149–160

Structured,e,f,g,h

Structurei,j,k

Drug category a b c d e f g h

k

153

i j

National Center for Biotechnology Information. PubChem compound database; CID = 6253, https://pubchem.ncbi.nlm.nih.gov/compound/6253 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 657237, https://pubchem.ncbi.nlm.nih.gov/compound/657237 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 20279, https://pubchem.ncbi.nlm.nih.gov/compound/20279 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 31703, https://pubchem.ncbi.nlm.nih.gov/compound/31703 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 30323, https://pubchem.ncbi.nlm.nih.gov/compound/30323 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 42890, https://pubchem.ncbi.nlm.nih.gov/compound/42890 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 4212, https://pubchem.ncbi.nlm.nih.gov/compound/4212 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 36462, https://pubchem.ncbi.nlm.nih.gov/compound/36462 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 9444, https://pubchem.ncbi.nlm.nih.gov/compound/9444 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 451668, https://pubchem.ncbi.nlm.nih.gov/compound/451668 (accessed Mar. 14, 2016). National Center for Biotechnology Information. PubChem compound database; CID = 216239, https://pubchem.ncbi.nlm.nih.gov/compound/216239 (accessed Mar. 14, 2016).

154

Table 2 Guideline-based chemotherapy regimens for relapsed/refractory acute myeloid leukaemia [1,8,22]. Example(s)

CR

Median Duration of Remission, DFS, or RFS

Median OS

Early death and/or treatment-related mortalitya

Nonhaematologic toxicities (grade/severity)

Non-intensive Regimens Low-dose cytarabine

Cytarabine 10 mg/m2 SC q 12 h × 21d [53]

38%–50% (refractoryrelapse) 21%

Not reported

Not reported

12% (induction deaths)

Infection (grade not specified)

6 months (time to relapse among patients achieving a response) Not reported

9 months

Not reported

Infection (grade 3–4)

177 days (overall), 209 days (decitabine alone), 107 days (decitabine plus gemtuzumab ozogamicin) 8.4 months

Not reported

Not reported

14% (early deaths)

6.2 months

9% (4-week mortality)

Septic episodes (infection or febrile neutropenia), bleeding (grade not specified) Dyspnoea, weight loss, vomiting, anorexia, rash, fatigue, hyperbilirubinaemia, abnormal creatinine, abnormal AST, abnormal ALT, hyperuricaemia, infection (all grade ≥3)

5 months (duration of unmaintained response)

Not reported

13% (induction deaths)

Photophobia or conjunctivitis, skin rash, nausea/vomiting, diarrhoea, abnormal liver chemistries (grade not specified); cerebellar dysfunction (grade ≤3)

9 months (HiDAC) 5 months (HiDAC + mitoxantrone) (RFS)

8 months (HiDAC) 6 months (HiDAC + mitoxantrone)

10% (HiDAC) 16% (HiDAC + mitoxantrone) (induction deaths)

Infection, neurologic toxicity + (HiDAC + mitoxantrone only) mucositis (all grade 3 or higher)

Hypomethylating agents (azacitidine or decitabine)

Hypomethylating agents (azacitidine or decitabine) + sorafenib (for FLT3-ITD mutations) Intensive Regimens HiDAC (if not received previously in treatment) ± anthracycline

Azacitidine 75 mg/m2 /d × 7d [54]

Decitabine 20 mg/m2 /d x 10d or × 5d + gemtuzumab ozogamicin [55]

15.7%

Azacitidine 75 mg/m2 /d × 5-7d [56]

10%

Azacitidine 75 mg/m2 /d × 7d + sorafenib 400 mg twice daily continuously [52]

16%

Cytarabine 3 g/m2 q 12 h × 12 doses ± doxorubicin 20 mg/m2 or daunorubicin 30 mg/m2 × 3d [51]

Overall: 53% Not resistant HiDAC: 63% HiDAC + A: 65% Resistant HiDAC: 20% HiDAC + A: 56% 32% (HiDAC) 44% (HiDAC + mitoxantrone)

Cytarabine 3 g/m2 q 12 h × 12 doses ± mitoxantrone 10 mg/m2 on days 7–9 [57]

13.4 months (duration of response) 2.3 months (duration of response)

J. Kell / Leukemia Research 47 (2016) 149–160

Recommendation

Mitoxantrone + etoposide

Etoposide + cytarabine ± mitoxantrone

61%

5 months (duration of remission)

6 months (for patients with CR)

9% (aplastic deaths)

Mitoxantrone 10 mg/m2 × 5d, etoposide 100 mg/m2 × 5d [59] Intermediate-dose cytarabine (1 g/m2 × 6d), etoposide 80 mg/m2 × 6d, mitoxantrone 6 mg/m2 × 6d [60]

32%

15+ months (duration of remission) 16 weeks (duration of remission)

∼6 months

3% (aplastic deaths)

36 weeks

6% (induction deaths)

55.3%

13 months (DFS)

9 months

10.5% (induction deaths)

53%

17 months (DFS)

9 months

7% (early deaths)

Infection, nausea and vomiting, diarrhoea, mucositis, bleeding, skin rash (all grade 3–4)

48%

15.5 months (duration of response)

Not reported

9.5% (early deaths)

46%

Not reported

9 months

0 (30-day mortality) 12% (treatment-related mortality)

Hyperbilirubinaemia, diarrhoea, skin rash, nausea/vomiting, increased creatinine/renal failure (all grade ≥3) Pulmonary, infection, hepatic transaminases, hyperbilirubinaemia, gastrointestinal, skin (all grade 3–4)

Fludarabine + cytarabine + G- Fludarabine 30 mg/m2 × 5d, cytarabine CSF ± idarubicin 2 g/m2 × 5d, G-CSF 5 mcg/kg Day 0 until neutrophil recovery [61] Cladribine + cytarabine + GCladribine CSF 5 mg/m2 × 5d + cytarabine 2 g/m2 × 5d + G-CSF 300 (CLAG) ± mitoxantrone (CLAG-M) or mcg × 6d + mitoxantrone idarubicin 10 mg/m2 × 3d [62] Clofarabine ± cytarabine + G- Clofarabine 15–30 mg/m2 × 5d, CSF ± idarubicin idarubicin 6–12 mg/m2 × 3d + cytarabine 0.75–1.0 mg/m2 × 5d [63] Clofarabine 15–25 mg/m2 × 5d, cytarabine 2 g/m2 × 5d, G-CSF 5 mcg/kg Day 0 until neutrophil recovery [64]

66%

Mucositis (grade 1–3), alopecia (all grade 3), nausea/vomiting (grade 1–2), diarrhoea (grade 1–2), hepatic toxicity (grade 1–2), weight loss (grade 1–2) Nausea, vomiting, mucositis, abnormal liver enzymes (all grade 3–4) Infection (severity not specified), fever of unknown origin (severity not specified), haemorrhage (mild to severe); nausea/vomiting (mild to severe), mucositis (mild to severe), liver toxicity (mild to severe), cardiac toxicity (mild to moderate) Infection, fever of unknown origin, mucositis, diarrhoea, hepatic toxicity, (all grade >3)

J. Kell / Leukemia Research 47 (2016) 149–160

Mitoxantrone 10 mg/m2 × 5d, etoposide 100 mg/m2 × 5d [58]

AE, adverse event; CR, complete remission; DFS, disease-free survival; FLT3-ITD, internal tandem duplication of FMS-like tyrosine kinase 3 gene; G-CSF, granulocyte colony stimulating factor; HiDAC, high-dose cytarabine; LFS, leukaemia-free survival; MEC, mitoxantrone, etoposide, and cytarabine; OS, overall survival; RFS, relapse-free survival. a Induction deaths, aplastic deaths or 30-day mortality, if specified.

155

156

J. Kell / Leukemia Research 47 (2016) 149–160

Relapsed/Refractory AML

Age Comorbidities Anthracycline dose Ejection fraction

Fit for Intensive Chemotherapy?

Yes

No

Re-induction

High-dose cytarabine

FlaG-Ida

Palliation

Low-dose cytarabine

Oral hydroxycarbamide

Repeat

Transplant Fig. 1. Clinical approach to treating patients with relapsed/refractory acute myeloid leukaemia.

patients, who comprise a substantial proportion of patients with rrAML, are particularly difficult and remain controversial. The challenge in treating rrAML is further underscored by the fact that treatment options for rrAML have not changed substantially in the past few decades, nor have studies been able to identify any combinations of existing agents that substantially improve outcomes. Clearly, new treatments are needed for this patient population. 4. Phase 3/late-stage investigational chemotherapy in rrAML Although searches of the literature (e.g., PubMed) and clinical trial databases (e.g., clinicaltrials.gov) show numerous studies of investigational agents (or combinations of existing agents) for treatment of rrAML, most have not been studied in Phase 3 clinical trials. Of the investigational Phase 3 treatments, positive results have been limited to date [72]. Further, interpretation of results from studies in rrAML tends to be confounded by the effects of subsequent therapy (e.g., HCT). Treatments with published Phase 3 study results include laromustine, clofarabine, elacytarabine, and vosaroxin. Table 3 [73–76]. provides an overview of these agents and Table 4 [73,74,77,78] summarises data from Phase 3 studies. 4.1. Laromustine Laromustine is a sulfonylhydrazine alkylating agent that has been studied in combination with cytarabine. A randomised, double-blind, Phase 3 study in patients with AML in first relapse compared laromustine + cytarabine (n = 178) and placebo + cytarabine (n = 90) [73]. Patients received cytarabine 1.5 g/m2 per day continuous IV infusion over 24 h on Days 1–3; laromustine (600 mg/m2 ) or placebo was administered intravenously over 30–60 min on Day 2. Overall response rates (CR plus CR without adequate platelet recovery [CRp]; primary outcome) were 35% among patients treated with laromustine + cytarabine and 19% among those treated with placebo + cytarabine (P = 0.005); CR rates were 20% and 16%, respectively. Paradoxically, within the laromustine + cytarabine arm, the highest CR rate was seen in

patients who were ≥60 years and had CR1 ≥12 months, whereas in the placebo + cytarabine group, the greatest CR rate was seen in patients who were <60 years and had CR1 ≥12 months or longer. Median OS was not significantly different between groups, but was about 1.5 months shorter in the laromustine + cytarabine group (128 days) than in the placebo + cytarabine group (176 days; P = 0.087). Also, the laromustine + cytarabine combination was associated with substantial mortality, primarily due to sepsis, pneumonia, and infection (30-day mortality rate: 11% vs 2% with placebo + cytarabine). Enrolment was stopped after an interim analysis at 50% enrolment due to concern that any potential CR benefit would be compromised by on-study mortality. Therefore, a revised protocol, with a lower dose of laromustine and mandatory growth factor support, was implemented; the results have not been published [73]. 4.2. Clofarabine Clofarabine is a second-generation deoxyadenosine analogue that has cytotoxic characteristics of fludarabine and cladribine, with a lower potential for dose-limiting toxicity [74]. It is currently included among salvage therapy regimens in NCCN guidelines (given with or without cytarabine and/or idarubicin) [1]. A randomised, double-blind, Phase 3 study (CLASSIC I) evaluated clofarabine + cytarabine compared with placebo + cytarabine in patients aged ≥55 years with rrAML [74]. The study included 320 patients (median age 67 years) with confirmed AML who received either clofarabine 40 mg/m2 or placebo, followed by cytarabine 1 g/m2 for 5 consecutive days [74]. Overall response rates (CR + CRi) were significantly higher in the clofarabine + cytarabine arm versus the placebo + cytarabine arm (46.9% vs 22.9%, respectively; P < 0.01), as were CR rates (35.2% vs 17.8%, respectively; P < 0.01). Evaluation of response rate by duration of CR1 and presence of the FLT3 mutation showed results similar to the total population. Median OS (primary endpoint) was 6.6 months in the clofarabine + cytarabine arm and was 6.3 months in the placebo + cytarabine arm (HR = 1.00; P = 1.00). EFS (HR, 0.63; 95% CI, 0.49–0.80; P < 0.01) favoured the clofarabine + cytarabine arm. However, overall 30-day mortality

J. Kell / Leukemia Research 47 (2016) 149–160

157

Table 3 Overview of Phase 3/late stage investigational chemotherapy agents for relapsed/refractory acute myeloid leukaemia. Agent

Laromustine

Clofarabine

Elacytarabine

Vosaroxin

Sulfonyl hydrazine alkylating agent [73]

Second-generation deoxyadenosine analogue [74]

Elaidic acid ester of cytarabine [75]

Anticancer quinolone derivative [76]

Structurea,b,c,d

Drug category

a National Center for Biotechnology Information. PubChem compound database; CID = 3081349, https://pubchem.ncbi.nlm.nih.gov/compound/3081349 (accessed Mar. 14, 2016). b National Center for Biotechnology Information. PubChem compound database; CID = 119182, https://pubchem.ncbi.nlm.nih.gov/compound/119182 (accessed Mar. 14, 2016). c National Center for Biotechnology Information. PubChem compound database; CID = 6438895, https://pubchem.ncbi.nlm.nih.gov/compound/6438895 (accessed Mar. 14, 2016). d National Center for Biotechnology Information. PubChem compound database; CID = 9952884, https://pubchem.ncbi.nlm.nih.gov/compound/9952884 (accessed Mar. 14, 2016).

was higher in the clofarabine + cytarabine arm (16%) compared with the placebo + cytarabine arm (5%; P < 0.01). The most common grade 3–4 toxicities (≥10% in the clofarabine + cytarabine arm) were febrile neutropenia, hypokalaemia, thrombocytopenia, pneumonia, anaemia, neutropenia, increased AST, and increased ALT; grade 3–4 acute renal failure occurred in eight patients (5%) treated with clofarabine + cytarabine but was not reported for any patients in the placebo + cytarabine arm. Although clofarabine + cytarabine significantly improved response rates and EFS, the primary end point of OS did not differ between arms, which may be due to a significantly higher rate of early mortality. 4.3. Elacytarabine Elacytarabine is an elaidic acid ester of cytarabine that is metabolised intracellularly to cytarabine; its mechanism of action is similar to that of cytarabine, but it has unique characteristics (eg, longer half-life, non-hENT1-dependent cell entry, longer intracellular distribution, and inhibition of DNA and RNA synthesis) that may help it to avoid cytarabine resistance [75]. In a randomised, open-label, Phase 3 trial, patients with rrAML (n = 381) were treated with elacytarabine (2 g/m2 /day—equivalent to 1 g cytarabine [79] continuous IV infusion × 5 days) or the investigator’s choice of treatment (see Table 2); the primary end point was OS [77]. The overall response rate (CR plus morphologic CR with incomplete blood count recovery [CRi]; 23% vs 21%) and CR rates (15% vs 12%) were similar between the elacytarabine and control arms, respectively. There was no significant difference in median OS (3.5 vs 3.3 months; HR = 0.97; P = 0.96) or in OS among any of the investigator’s choice regimens. Subgroup analysis of OS by patient or AML characteristics did not show any differences in outcome. Median relapse-free survival (5.1 vs 3.7 months) and 30-day mortality rates (17% vs 15%) were similar between the elacytarabine and control arms, respectively. The most frequently occurring nonhaematologic adverse events in the elacytarabine arm were nausea, pyrexia, hypokalaemia, diarrhoea, vomiting, hyperbilirubinaemia, headache, constipation, decreased appetite, and febrile neutropenia. Elacytarabine was associated with significantly higher rates of grade 3/4 hyperbilirubinaemia (14% vs 3%; P < 0.001), elevated ALT (11% vs 4%; P = 0.007), and hypercholesterolaemia (12% vs 0%; P < 0.001); these abnormalities were transient in most patients and likely due to the phospholipid-containing liposomes used in elacytarabine.

4.4. Vosaroxin Vosaroxin is a first-in-class anticancer quinolone derivative with a unique mechanism of action and drug-resistance profile that are distinct from those of other anticancer agents [80,81]. Vosaroxin induces replication-dependent DNA damage by intercalating into DNA and blocking topoisomerase II-mediated religation, ultimately leading to apoptosis [76]. Due to quinolone core stability, vosaroxin is minimally metabolised, resulting in low potential for drug-drug interactions or production of off-target reactive oxygen species [76,82,83]. It also evades P-glycoprotein receptor–mediated efflux [84] and has activity independent of p53 status [81]. A Phase 3, randomised, double-blind, multicentre trial (VALOR) compared vosaroxin + cytarabine (n = 356) vs placebo + cytarabine (n = 355) in patients aged ≥18 years with first rrAML, using an adaptive design [78]. Patients received vosaroxin (90 mg/m2 in cycle 1 and 70 mg/m2 in subsequent cycles by short [within 10 min] IV infusion on Days 1 and 4) or placebo in combination with cytarabine (1 g/m2 , 2-h infusion on Days 1–5). Combined CR (CR, CR without complete platelet recovery [CRp], and CR with incomplete recovery of platelets or neutrophils [CRi]) rates (37% vs 19%; P < 0.0001) and CR rates (30% vs 16%, P < 0.0001) were significantly higher for patients treated with vosaroxin + cytarabine versus placebo + cytarabine. Median OS (primary efficacy endpoint) was 7.5 months for vosaroxin + cytarabine compared to 6.1 months for placebo + cytarabine (HR = 0.87, unstratified P = 0.061; stratified P = 0.024). In a predefined analysis of OS censoring for later stem cell transplantation, patients receiving the vosaroxin combination had a median OS of 6.7 months versus 5.3 months for placebo + cytarabine (HR = 0.81, unstratified P = 0.024; stratified P = 0.027). OS benefit with vosaroxin was greatest in patients age ≥60 years (7.1 months vs 5.0 months with placebo + cytarabine; unstratified P = 0.0030) and those with early relapse (6.7 months vs 5.2 months; unstratified P = 0.039). Median EFS was significantly longer at 1.9 months in the vosaroxin + cytarabine group versus 1.3 months in the placebo + cytarabine group (HR 0.67 [95% CI: 0.57–0.79]; P < 0.0001). Thirty-day all-cause mortality was similar for the vosaroxin + cytarabine and placebo + cytarabine groups (8% and 7%, respectively). The most common grade 3 and higher AEs were primarily related to myelosuppression, infection, and

158

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Table 4 Summary of Phase 3 data for investigational agents in the treatment of refractory or relapsed acute myeloid leukaemia.

Giles et al 2009 [73] Laromustine + cytarabine

Placebo + cytarabine

Regimen

CR

Median duration of Remission, Time to Relapse, or DFS/LFS

Median OS

Early death (30-day mortality)

Most common grade ≥3 AEs (incidence ≥10%) for investigational treatment

Cytarabine 1.5 g/m2 /day × 3d + laromustine 600 mg/m2 on Day 2 Cytarabine 1.5 g/m2 /day × 3d + placebo on Day 2

Overall response (CR + CRp): 35% [P = 0.005] CR: 20% [P value not reported] Overall response (CR + CRp): 19% CR: 16%

275 days (duration of response [CR + CRp]) [P = 0.640] 332 days

128 days [P = 0.087]

11% [P = 0.016]

Febrile neutropenia, dyspnea, hypokalaemia, hypoxia

176 days

2%

Overall remission (CR + CRi): 47% [P < 0.01] CR: 35% [P < 0.01]

8.1 months (DFS in patients who achieved CR or CRi)

6.6 months [P = 1.00]

16% [P < 0.01]

Overall remission (CR + CRi): 23% CR: 18%

7.0 months

6.3 months

5%

Overall response (CR + CRi): 23% CR: 15%

11.6 months (time to relapse in patients who achieved CR)

3.5 months [P = 0.96]

17%

Overall response (CR + CRi): 21% CR: 12%

Not reached

3.3 months

15%

Combined response (CR + CRp + CRi): 37% [P < 0.0001] CR: 30% [P < 0.0001]

11.0 months (LFS in patients with CR) [P = 0.63]

8%

Combined response (CR + CRp + CRi): 19% CR: 16%

8.7 months

7.5 months [unstratified P = 0.061; stratified P = 0.024] 6.1 months

Faderl et al 2012 [74] Clofarabine + Clofarabine 40 mg/m2 , then cytarabine cytarabine 1 g/m2 × 5d

Placebo + cytarabine

Placebo, then cytarabine 1 g/m2 × 5d

Roboz et al 2014 [77] Elacytarabine Elacytarabine 2 g/m2 /day × 5d

Control

Investigator’s choice: HiDAC, MEC, FlaG/FlaG-Ida, LDAC, hypomethylating agents, hydroxyurea, best supportive care

Ravandi et al 2015 [78] Vosaroxin + Vosaroxin 90 mg/m2 (in cycle 1; 70 mg/m2 in cytarabine subsequent cycles) on Days 1 and 4 + cytarabine 1 g/m2 × 5d Placebo + cytarabine

Placebo on Days 1 and 4 + cytarabine 1 g/m2 × 5d

Febrile neutropenia, hypokalaemia, thrombocytopenia, pneumonia, anaemia, neutropenia, increased AST, and increased ALT

Febrile neutropenia, neutropenia, thrombocytopenia, leukopenia, anaemia, hyperbilirubinaemia, hypokalaemia, hypercholesterolaemia, ALT increased

Febrile neutropenia, anaemia, thrombocytopenia, neutropenia, stomatitis, pneumonia, sepsis, bacteraemia, hypokalaemia

7%

AE, adverse event; CR, complete remission; CRi, CR with incomplete recovery of platelets or neutrophils; CRp, CR with incomplete recovery of platelets; DFS, disease-free survival; FlaG/FlaG-Ida, fludarabine, cytarabine, and G-CSF ± idarubicin; HiDAC, high-dose cytarabine (e.g., 1–6 g/m2 /day × ≤6 days [max total dose 36 g/m2 ]); LDAC, low-dose cytarabine (≤40 mg/day); LFS, leukaemia-free survival; MEC, mitoxantrone, etoposide, and cytarabine; OS, overall survival.

gastrointestinal events. The combination of vosaroxin and cytarabine increased OS and CR rates without worsening early mortality.

remain complex due to the heterogeneity in terms of AML itself, patient characteristics, and initial treatment. Acknowledgement

5. Conclusion As research has enhanced the understanding of numerous factors influencing efficacy outcomes, as well as toxicity and tolerability, it is becoming possible to identify patients who are likely to respond well to currently available salvage treatments for rrAML. However, new treatments are needed, especially for older patients who may not tolerate standard chemotherapy and for patients with negative prognostic factors. Although obtaining CR is vital to achieving the overall goal of more durable disease control, it is equally important that patients emerge from salvage therapy in adequate condition to tolerate subsequent HCT or additional intensive treatments. One or more agents in late-stage development may provide useful options for this patient population for which a significant unmet medical need exists. Even with the development of new drug therapies, treatment decisions for patients with rrAML

The authors thank Sherri D. Jones, PharmD, of MedVal Scientific Information Services, LLC, for providing medical writing and editorial assistance. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines.” Funding to support this study and the preparation of this manuscript was provided by Sunesis Pharmaceuticals. References [1] National Comprehensive Cancer Network, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ): Acute Myeloid Leukemia. Version 1.2016, National Comprehensive Cancer Network, Fort Washington, PA, 2016 (Feb 16). [2] National Cancer Institute, SEER stat fact sheets: acute myeloid leukemia. Available at: http://seer.cancer.gov/statfacts/html/amyl.html Accessed October 23, 2015.

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