Chemotherapeutic Treatment of Acute Myeloid Leukemia
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Clinical Trial Outcomes Mahdi, Mahdi & Knapper Chemotherapeutic treatment of acute myeloid leukemia 5 Clinical Trial Outcomes Chemotherapeutic treatment of acute myeloid leukemia: incorporating the results of recent clinical trials Clin. Invest. (Lond.) Better outcomes for patients with acute myeloid leukemia over the last 30 years have Ali J Mahdi*,1, Eamon J been largely achieved by improvements in supportive care measures rather than Mahdi1 & Steven Knapper1 therapeutic advances. The combination of daunorubicin and cytarabine has remained 1Cardiff University School of Medicine, Hematology Department, Heath Park, the standard of care for patients undergoing intensive induction–consolidation Cardiff CF14 4XN, UK treatment. In less fit older patients, low-dose cytarabine is the equivalent, although *Author for correspondence: the hypomethylating agent azacitidine may be challenging current practice. [email protected] Enhanced understanding of disease pathogenesis and therapy resistance has enabled the entry of novel chemotherapeutic and nonchemotherapeutic agents into clinical development with varied levels of activity. This article examines the evidence behind established chemotherapy practices for intensive and nonintensive acute myeloid leukemia treatments with an emphasis on emerging clinical trial data from novel chemotherapeutic and nonchemotherapeutic agents. Keywords: acute myeloid leukemia • aminopeptidase inhibitors • farnesyl transferase inhibitors • FLT3 inhibitors • gemtuzumab ozogamicin • histone deacytylase inhibitors • hypomethylating • Polo-like kinase 1 inhibitors Methodology AML cases [7]. Older patients over the age of 10.4155/CLI.14.112 An electronic database search (EMBASE, 60 years thus represent an important popula- MEDLINE and PubMed) was undertaken tion from both demographic and therapeutic to identify and review clinical studies in perspectives. Older patients frequently have acute myeloid leukemia (AML) undertaken multiple comorbidities, unfavorable cyto- between 1 January 2009 and 1 June 2014. genetic and molecular profiles, pre-existing myelodysplasia and poor performance status 1 Background and, as a result, have poor tolerability and The treatment of AML has remained resistance to standard chemotherapy with far immensely challenging for clinicians due to inferior outcomes. Only 40–50% of those the disease’s heterogeneity and the multiple over 60 years of age with a good performance 2015 confounding factors that influence its prog- status achieve a complete remission (CR), and nostic landscape. Younger patients, generally cure rates remain less than 10% and median defined as those aged less than 60 years, have survival is less than 1 year [8,9]. seen sustained increases in survival as a result Improvements in the understanding of the of improved supportive care measures, better molecular biology of AML using techniques risk stratification and developments in stem such as gene expression profiling and miRNA cell transplantation [1–3] . Despite approxi- platforms has helped to further delineate mately 70–80% of these patients achieving prognosis. This is particularly important for complete remission [4,5], the majority still patients with a normal karyotype who com- ultimately relapse and overall survival (OS) prise 40% of the total AML patients [11,12]. remains only 40–45% at 5 years [6]. However, From such developments, the isolation of this age group only accounts for a third of all novel targets to manipulate and control part of 10.4155/CLI.14.112 © 2015 Future Science Ltd Clin. Invest. (Lond.) (2015) 5(1), 89–110 ISSN 2041-6792 89 Clinical Trial Outcomes Mahdi, Mahdi & Knapper driving factors in the disease has been possible. A and cytarabine (DA). This combination is classically simple model that exemplifies this can be found in the delivered using the ‘3 + 7’ schedule, in which dau- APL-RARA fusion protein underlying the pathogen- norubicin (45–60 mg/m2) is administered for 3 days esis of acute promyelocytic leukemia. Knowledge and, with a continuous infusion of cytarabine (AraC; importantly, inhibition of this pathway have resulted in 100–200 mg/m2) over 7 days. There have been many superior outcomes [13,14] for acute promyelocytic leuke- variations on this theme, with the MRC AML tri- mia (APL) patients. Other AML entities are, however, als employing a ‘3 + 10’ approach. Attempts to aug- genetically far more heterogeneous, with complex inter- ment and/or manipulate this standard ‘backbone’ actions between numerous cell surface and intracellular combination have met with variable success. pathways; the concept of targeting leukemic cells and Dose intensification of daunorubicin (45 vs sparing normal cells from the unselected attack of che- 90 mg/m2) has been extensively studied. The East- motherapy, while appealing, remains problematic, as ern Cooperative Onclology Group (ECOG) 1900 there are multiple potential targets in AML cells that trial showed improved CR rates in younger patients may require simultaneous targeting [6]. Recent genomic (<60 years of age) treated with higher doses (71 vs analyses have emphasized the genetic complexity of 57%; p < 0.001) with no excess toxicity [24]. A Korean AML with at least one potential driver mutation and study noted similar outcomes regarding CR rate (82 vs a complex interplay of genetic events contributing to 72%; p = 0.014) and toxicity [25]. The HOVON-SAKK AML pathogenesis [15] . study of patients aged 60–83 years also demonstrated Traditional trial design, involving drug safety benefit with superior CR rates (64 vs 54%; p = 0.014), (Phase I), suggestion of efficacy (Phase II) and true effi- but the survival benefit was only demonstrated in the cacy, survival and quality of life effects (Phase III), is 60–65 years of age subgroup [26]. Despite these prom- still deep rooted in clinical practice. This approach may ising data, caution needs to be exercised before dauno- hinder efficiency and increase the costs of drug devel- rubicin 90 mg/m2 is established as the new standard opment in AML, especially with the ever-expanding of care; similar rates of survival have been reported number of targets and molecules being developed. To in trials featuring conventional-dose daunorubicin, overcome this, selection ‘pick-a-winner’ trials, screening including the MRC AML12 and 15 studies, in wihch trials and randomized discontinuation trials have been patients received daunorubicin 50 mg/m2, but for two 2 developed [16–18]. The MRC trials for older patients courses, giving a cumulative dose of 300 mg/m [27]. with untreated AML now employ the pick-a-winner The National Cancer Research Institute (NCRI) design [19] . In these trials, the goal is to select therapies AML17 study of younger patients continues to address with superior early responses for further testing, with the anthracycline dose intensification question by early rejection of unpromising agents based on a strict comparing intermediate- with high-dose daunorubicin 2 statistical algorithm [17] . Despite this shift in design, (60 and 90 mg/m ) in the first induction followed by a other limiting factors remain problematic to the collec- second course of 50 mg/m2. tion of reliable data. Most notably, these include small ‘High-dose AraC’ (HDAC) generally refers to a sample sizes, poor patient recruitment, lack of a control AraC dose of 1000–3000 mg/m2. The use of HDAC group, patient heterogeneity and the use of surrogate in induction achieved no improvement in CR rates end points that do not predict clinical benefit [19] . and OS with increased toxicity in comparison to In this article, we aim to present and critically evalu- standard-dose AraC in a randomized trial of 860 ate the data published over the past 10 years using novel patients (<60 years of age) comparing 200–1000 and chemotherapeutic and targeted agents in AML. To 1000–2000 mg/m2 of AraC over two cycles given, provide context, the historical evidence underpinning respectively, with idarubicin and amsacrine cycles 1 established induction–remission approaches will also and 2. CR rates (82 vs 80%; p = 0.45), OS (42 vs 40%; be summarized. Judicious use of allogeneic bone mar- p = 0.87) and event-free survival (35 vs 34%; p = 0.79) row transplantation (allo-SCT) remains central to the were similar between the two groups, but grade 3–4 management of selected patients, but in-depth analy- adverse events were increased in those receiving HDAC ses of transplantation or of the management of APL (61 vs 51%; p = 0.005) [28]. are beyond the scope of this article, and the reader is Studies analyzing the addition of agents such as directed to other reviews of these areas [20–23]. etoposide or 6-thioguanine to the DA backbone have generally been disappointing. The MRC AML15 trial Evidence base for current induction randomized 2673 younger adults between standard strategies DA, DA plus etoposide (ADE) and fludarabine, AraC, The mainstay of treatment for AML over the past G-CSF and idarubicin (FLAG-Ida) [29]. Induction CR 40 years has been the combination of daunorubicin rates were similar across the three groups (DA: 72% vs 90 Clin. Invest. (Lond.) (2015) 5(1) future science group Chemotherapeutic treatment of acute myeloid leukemia Clinical Trial Outcomes ADE: 82% vs FLAG-Ida: 84%), with greater toxicity AraC [27]. Equally, the NCRI AML15 trial demon- seen in the ADE and FLAG-Ida groups. Although strated no survival difference between a total of four relapse rates in the FLAG-Ida group were lower, no and five cycles of therapy in younger patients. difference in OS was seen. The addition of mitoxantrone and daunorubicin to The Polish Acute Leukemia Study Group demon- an attenuated dose of AraC in consolidation has shown strated a potential benefit from the addition of cladrib- no significant overall benefit, although in the NCRI ine to DA in two randomized clinical trials [30,31] . In the AML15 trial, an amsacrine–etoposide–mitoxantrone- larger trial, of 652 younger (<60 years of age) patients, based consolidation approach proved superior to both DA was compared with DA plus cladribine (DAC; HDAC dose levels (1.5 and 3 g/m2) in patients with 2 5 mg/m , days 1–5) and DA plus fludarabine (DAF; poor-risk cytogenetics [34].