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. 2014 Dec;5(6):211–220. doi: 10.1177/2040620714552615

Clinical potential of elacytarabine in patients with acute myeloid leukemia

Lindsay A M Rein 1, David A Rizzieri 2,✉
PMCID: PMC4250268  PMID: 25469211

Abstract

Acute myeloid leukemia (AML) has been treated for over four decades with standard induction chemotherapy including seven days of cytosine arabinoside (cytarabine, ara-C) infusion. Cytarabine, while effective in killing leukemic cells, is subject to development of several resistance mechanisms rendering the drug ineffective in many patients. Elacytarabine, a lipophilic 5’-elaidic acid ester or nucleoside analogue of cytosine arabinoside, was created with the intent of overcoming resistance mechanisms including reduced expression of the human equilibrative nucleoside transporter 1 (hENT1) required for cytarabine entry into cells, as well as increased activity of cytidine deaminase (CDA) which breaks down the active metabolite of cytarabine, ara-CTP. Elacytarabine enters cells independently of transporters, has a longer half life compared with cytarabine and is not subject to deactivation by CDA. Preclinical data were encouraging although subsequent clinical studies have failed to show superiority of elacytarabine compared with standard of care as monotherapy in patients with AML. Clinical trials utilizing elacytarabine in combination with anthracyclines are ongoing. Use of hENT1 expression as a predictive marker for cytarabine or elacytarabine response has been studied with no conclusive validation to date. Despite promising early results, the jury is still out in regards to this novel agent as an effective alternative to standard cytarabine therapy in acute leukemias, especially in combination with additional agents such as anthracyclines.

Keywords: elacytarabine, acute myeloid leukemia, therapy

Introduction

Acute myeloid leukemia (AML) is a heterogeneous and complex group of diseases with an annual incidence of 3–5 cases per 100,000 of the US population. It is characterized by clonal proliferation of myeloid precursors and associated reduced capacity of these cells to differentiate into mature cells. [Vardiman et al. 2009; Smith et al. 2011; Dores et al. 2012]. Unfortunately, little has changed over the past four decades in terms of survival rates. Despite an extensive literature of leukemia biology, several additions to the treatment options available for acute leukemias and rich molecular characterization of this group of diseases, we continue to treat patients both for induction and in relapse with cytosine arabinoside (cytarabine or ara-C) based regimens [Giles et al. 2006; Zhu et al. 2010].

Nucleoside analogues such as cytarabine, fludarabine, decitabine and gemcitabine have been cornerstones of therapy in several hematologic malignancies including chronic lymphocytic leukemia, myelodysplastic syndromes, mantle cell lymphoma and AML as well as in several chemotherapeutic regimens for solid tumors [Burnett et al. 2011; Jordheim et al. 2013]. Cytarabine, in particular, has been a well established part of induction chemotherapy for AML since its original approval date in 1969 as part of ‘7+3’ or cytarabine plus a topoisomerase II inhibitor. Due to the heterogeneous nature of AML and the multiple mechanisms of resistance, cure is still elusive in this disease. Therefore, alternative strategies to optimize use of this effective class of chemotherapeutic agents are necessary.

Elacytarabine or CP-4055 is a novel cytotoxic nucleoside analogue which has mechanisms of action similar to those of cytarabine, but with some advantages. It was originally designed with the goal of being able to circumvent cytarabine resistance, with novel mechanisms of action working independent of nucleoside transporters, and demonstrated promising results in preclinical and early clinical data. However, more advanced clinical data have not been as encouraging.

In this review, we discuss cytarabine as the parent drug to elacytarabine along with mechanisms of action and mechanisms of resistance. We also discuss the pharmacology of elacytarabine, preclinical data supporting translation into the clinic as well as the current state of clinical trial data with use of this novel chemotherapeutic agent.

Cytarabine: parent drug

Pharmacology and mechanism of action

Cytosine arabinoside, otherwise known as cytarabine, ara-C or 1-beta-D-arabinofuranosylcytosine, has been a part of the chemotherapy backbone for induction of patients with newly diagnosed AML for more than four decades. It has also been extensively studied for treatment of relapsed or refractory disease, as consolidation therapy in AML at high doses and in pediatric patients [Ganesan et al. 1987; Lister et al. 1987; Hiddemann, 1991]. The activity of cytarabine varies among the different types of leukemias, in part, due to doses and methods of administration and mechanisms of resistance altering efficacy in different patients with no proven means of predicting who will respond [Galmarini et al. 2002a].

The pharmacology of cytarabine is both unique and complex. Cytarabine enters the plasma where it can be metabolized in one of two ways. It can be rapidly deaminated by cytidine deaminase (CDA) into inactive metabolite or uracil arabinoside (ara-U). Cytarabine can also be taken up into target cells through specialized nucleoside transporter proteins, most commonly human equilibrative nucleoside transporter 1 (hENT1), where it is phosphorylated by deoxycytidine kinase (DCK) into active triphosphate metabolite, ara-C triphosphate (ara-CTP) [Grant, 1998]. Cytarabine is converted first to ara-C monophosphate (ara-CMP) which is then phosphorylated into ara-C diphosphate (ara-CDP) which then is phosphorylated once again by diphosphate kinases into ara-CTP [Hande et al. 1978]. Ara-CTP incorporates into DNA and leads to cellular death and subsequent clinical benefit [Ho, 1973; Plagemann et al. 1978]. Based on pharmacodynamic data, a critical factor influencing response to therapy is the time cytarabine is retained by target cells or leukemic blasts [Preisler et al. 1985; Rustum et al. 1992; Reese et al. 2013]. Therefore, several strategies such as lipid vector technology (as described below) have been employed to alter the metabolism of older chemotherapeutics, thus maximizing efficacy of the drug.

Altered dosing and methods of administration of cytarabine affect cellular metabolism and mechanism of uptake of the drug. Cytarabine is taken up into cells by hENT transporter protein when given at lower doses such as those used in standard ‘7+3’ leukemia regimens. When given at higher doses, such as those often utilized in consolidation therapy, cytarabine achieves higher plasma concentration and is able to passively diffuse into cells [Weinstein et al. 1982; Spriggs et al. 1985]. The ability to saturate and bypass hENT1 with high doses of cytarabine provides the rationale for use of high dose cytarabine in patients with relapsed or refractory disease as a potential mechanism of bypassing resistance [Pastor-Anglada et al. 2005]. Unfortunately, higher dosing with associated higher plasma concentrations of drug also leads to increased toxicity. Due to the speed with which cytarabine is metabolized to inactive metabolites when it is originally exposed to plasma, cytarabine is often given as a continuous infusion or infusions over 3 hours. Several studies suggest that duration of ara-CTP retention in leukemic blasts is the most important factor influencing response [Preisler et al. 1985]. Because the metabolism of cytarabine is complex and cancer cells are savvy to evade chemotherapeutic agents, various steps of metabolism can be rendered susceptible to alteration thus leading to development of resistance mechanisms.

Mechanisms of resistance

Several mechanisms of resistance to cytarabine have been described including inefficient cellular uptake of drug into cells, reduced levels of activating enzymes and increased degradation of active metabolite. There are several rate limiting steps in the conversion of parent drug to active metabolite which have all been implicated in the development of resistance.

Inefficient cellular uptake

Nucleoside analogues do not passively diffuse well into target cells and require transporter proteins to efficiently enter cells. Interestingly, hENT1 accounts for 80% of cytarabine influx into leukemic blasts [Sundaram et al. 2001]. Loss of function mutations in hENT1 have been implicated in cytarabine resistance both in vivo and in vitro [Cai et al. 2008]. Takagaki and colleagues looked at gene expression profiling in cytarabine resistant cell lines in comparison with wild type cells. In cytarabine resistant cell lines, adenosine deaminase (ADA) gene expression was upregulated while hENT1 expression along with expression of several cell-cycle related genes was downregulated [Takagaki et al. 2004].

Clinically, decreased hENT1 expression of any etiology seems to be associated with altered patient outcomes. Several groups have reported that reduced hENT1 expression can be associated with worse outcomes in patients with AML treated with cytarabine. Hubeek and colleagues studied mRNA expression of enzymes involved in the metabolism of cytarabine as measured by quantitative real time polymerase chain reaction (PCR) in pediatric patients with newly diagnosed AML in vitro. They found decreased hENT1 expression in patients with resistant disease and this also predicted for cytarabine resistance [Hubeek et al. 2005]. Galmarini and colleagues showed that hENT1 deficiency predicts for a shorter disease free survival in adult patients with AML as well as increased rate of relapse and decreased overall survival [Galmarini et al. 2002a, 2002b]. More recently, Jin and colleagues assessed cytarabine resistance in FLT3-ITD positive AML cells and found that the FLT3-ITD mutation, classically associated with poor prognosis disease, suppresses hENT1 expression, perhaps accounting for the lower response of FLT3 positive patients to induction chemotherapy [Jin et al. 2009]. In contrast, Stam and colleagues measured expression of cytarabine metabolizing enzymes by quantitative PCR and demonstrated that increased hENT1 expression predicts sensitivity to cytarabine in infants with MLL gene-rearranged acute lymphoblastic leukemia (ALL) [Stam et al. 2003]. These data support the relationship between cytarabine resistance and hENT1 expression, and suggest that hENT1 expression may be used clinically as a predictor of cytarabine response although further validation of the marker is needed.

Altered transporter protein expression, notably decreased hENT1, has important implications not only with cytarabine but also with other nucleoside analogues. This includes decitabine used to treat myelodysplastic syndromes, fludarabine used to treat chronic lymphocytic leukemia and other lymphomas, and gemcitabine used to treat mantle cell lymphoma and several solid tumor malignancies such as pancreatic, gastric and lung cancer [Mackey et al. 2005; Marce et al. 2006; Oguri et al. 2007; Qin et al. 2009]. Therefore, overcoming inefficient cellular uptake by hENT may be applicable to several groups of patients with various malignancies.

Reduced levels of activating enzymes

Several enzymes are involved in the intracellular metabolism of cytarabine to its active form, ara-CTP. As described above, DCK phosphorylates cytarabine into active triphosphate metabolite. DCK conversion of cytarabine into ara-CMP appears to be a rate limiting step of drug metabolism and is also a frequent target for development of drug resistance [Plunkett et al. 1985]. Loss of function mutations in DCK have been shown to cause cytarabine resistance in vitro and in vivo and Cai and colleagues have shown that decreased expression of DCK mRNA is associated with decreased DCK activity and increased cellular resistance to cytarabine [Damaraju et al. 2003; Cai et al. 2008]. Both complete and partial loss of enzyme can lead to resistance and several have shown that restoration of DCK levels can restore sensitivity to nucleoside analogues [Stegmann et al. 1995]. Conversely, nucleophosmin (NPM) gene mutations, classically associated with better AML prognosis, have been shown to be associated with increased DCK transcription [Keane et al. 2013].

Increased degradation of active metabolite

Active cytarabine metabolite, ara-CTP, can also be degraded with subsequent decreased drug activity. As part of normal drug metabolism, a portion of infused cytarabine will be deactivated when deaminated by CDA [Laliberte et al. 1994]. As expected, increased levels of CDA in AML cells lead to increased cytarabine resistance [Abraham et al. 2012]. Lower levels of ara-CTP can also occur when ara-CMP is dephosphorylated by pyrimidine nucleotidase I (PN-1) or when it is deaminated by deoxycytidylate deaminase (dCMPD) [Mancini et al. 1983].

All three mechanisms of resistance as described above are well established with cytarabine and other nucleoside analogues. Therefore, alternative strategies to modify existing agents as well as to develop novel therapeutics and avoid resistance have been developed.

Elacytarabine: modified chemotherapeutic agent

With hopes of developing ways to circumvent cytarabine resistance and increasing cellular retention times, a lipophilic 5′-elaidic acid ester or nucleoside analogue of cytarabine known as elacytarabine (CP-4055) was developed. This drug enters cells independently of hENT1 and has demonstrated activity in cytarabine-resistant cell lines and animal models of resistant disease. Lipid vector technology, in general, has been a novel technique which has allowed scientists and physicians to capitalize on known effective therapies while bypassing resistance mechanisms.

Mechanism of action

Elacytarabine is an elaidic acid ester of cytarabine which is metabolized intracellularly to cytarabine. The mechanism of action is similar to that of cytarabine, although elacytarabine has several additional advantageous characteristics including longer half life, prolonged intracellular distribution, inhibition of both DNA and RNA synthesis, and ability to enter cells independent of hENT1 which make it unique and potentially immune to mechanisms of resistance seen with classic cytarabine. Several in vitro and in vivo studies have illustrated potential benefit to this modified therapeutic and have allowed us to bring this drug to clinical trials as described below.

Preclinical studies

In vitro studies

Work dating back to the 1970s and 1980s has suggested that modification of cytarabine by encapsulating it into liposomes or by direct incorporation of the lipophilic drug into lipid membranes of liposomes increases efficacy of the drug by preventing degradation and systemic elimination. This has previously been demonstrated in several solid tumors as well as in lymphoma models of disease [Rustum et al. 1979; Richardson et al. 1982; Richardson and Ryman, 1982; Rubas et al. 1986].

Elacytarabine is unique compared to cytarabine due to the fact that it enters target cells independent of hENT transporter proteins. In 2009, Galmarini et al. studied CP-4055, now known as elacytarabine, and CP-4126, the 5′-elaidic acid ester of gemcitabine, in cell lines. Sensitivity profiles of both drugs were compared to profiles of cytarabine and gemcitabine in lymphoma cell lines which were either proficient or deficient in membrane transporters. Transporter proficient cell lines showed equal activity of CP-4055, CP-4126, cytarabine and gemcitabine while transporter deficient cell lines were highly resistant to standard cytarabine and gemcitabine, although more sensitive to CP-4055 and CP-4126. Transporter proficient cell lines were then exposed to nitrobenzylthioinosine (NBTI), an hENT1 inhibitor. NBTI treated transporter proficient cell lines were resistant to cytarabine and gemcitabine and were sensitive to CP-4055 and CP-4126 allowing authors to conclude that newer therapeutics were able to overcome resistance mechanisms in vitro [Galmarini et al. 2009].

Once taken up at the cellular membrane, elacytarabine must be metabolized or converted to cytarabine, which is subsequently phosphorylated and converted into active ara-CTP. In several papers, Bergman and colleagues suggested that elacytarabine may be more effective than cytarabine due to prolonged retention of elacytarabine and its active downstream products with increased interruption of DNA synthesis in vitro. Using a murine colon cancer line and the counterpart line resistant to gemcitabine, the authors demonstrated that CP-4055 prevented deamination or breakdown of active metabolite of cytarabine in both cells lines and prevented DNA synthesis for longer periods of time compared with active parent drug. Interestingly, CP-4055 also inhibited RNA synthesis, which was not seen using cytarabine and had increased retention time inside the target cells compared with cytarabine [Bergman et al. 2004a, 2004c]. Adema and colleagues also assessed metabolism of elacytarabine and CP-4126, and found that both drugs localized to the cellular membrane and cytosolic fraction which may, in part, account for increased cellular retention of active drug metabolites which was also observed in this study [Adema et al. 2012]. Others have suggested that increased exposure of cells to active cytarabine metabolite when treated with elacytarabine compared with standard cytarabine may also be due to resistance of elacytarabine to degradation by CDA and subsequent conversion to inactive metabolite which has been demonstrated in cell lines from both leukemia as well as solid tumors [Bergman et al. 2004b].

In addition to assessing the effects of elacytarabine in cell lines, several studies have also looked at effects of elacytarabine in combination with other chemotherapeutic agents. Adema and colleagues studied the role of docetaxel, oxaliplatin and pemetrexed in combination with CP-4055 and CP-4126 in vitro using lung and colon cancer cell lines. CP-4055 plus oxaliplatin showed synergistic effects, and preincubation of cells with docetaxel increased cellular killing in both lung and colon cancer cells lines when used in combination with CP-4055. There were no noted effects of combination therapy with pemetrexed [Adema et al. 2010]. These data suggested that elacytarabine may be effective as combination therapy.

Adams and colleagues went on to study alternative combination therapy of elacytarabine plus gemcitabine, irinotecan, topotecan, cloretazine and idarubicin in both lymphoma and acute promyelocytic cell lines. Using the combination index and combination effect methods, this study aimed to assess for drug combinations which may best affect cells or have synergistic effects. CP-4055 had antiproliferative effects in both cell lines used including HL60 (acute promyelocytic leukemia cell line) and U937 (lymphoma cell line) cells, and CP-4055 in combination with all other therapeutics as listed above were synergistic or additive in all combinations of therapy and in both cell lines [Adams et al. 2008].

These in vitro data demonstrated that elacytarabine and other lipophilic 5′-elaidic acid esters or nucleoside analogues have effects, and often increased effect, in cell lines and provided the foundation for moving these therapeutics into animal models and ultimately into human studies.

In vitro studies

There are strong in vitro data to support activity of elacytarabine in leukemia with likely ability to bypass several known resistance mechanisms plaguing its parent compound. In vivo data in several mouse models of disease including leukemia, lymphoma and several solid tumors are even more convincing.

In the study by Adema and colleagues of CP-4055 in combination with docetaxel or pemetrexed as described above, xenograft models of colon cancer and lung metastasis were also utilized to assess efficacy of combination therapy. Interestingly, docetaxel plus CP-4055 dual therapy led to decreased metastasis in the lung cancer model with an associated favorable side effect profile, again confirming potential benefit of combination therapy [Adema et al. 2010].

Breistol and colleagues went on to compare elacytarabine to cytarabine in human tumor xenograft models and demonstrated impressive results. Using a Raji Burkitt’s lymphoma model in nude rats, the investigators demonstrated that animals treated with normal saline or cytarabine had a mean survival of 13.2 days while animals treated with CP-4055 had mean survival of greater than 70 days. Similar findings of significantly improved survival were demonstrated using a systemic Raji leukemia model when comparing cytarabine and saline versus elacytarabine. Solid tumor xenograft models including melanoma, breast cancer, non-small cell lung cancer and osteogenic sarcoma were also used and, interestingly, partial or complete tumor regression was seen in lung cancer and melanoma models after treatment with elacytarabine. This was in contrast to cytarabine which did not affect tumor growth [Breistol et al. 1999].

Several other animal studies demonstrated potential benefit of elacytarabine both as monotherapy as well as in combination with other chemotherapeutic agents, thus providing the basis for trials of this therapeutic in patients.

Clinical trials

Several studies have been conducted to date to assess the efficacy of elacytarabine in patients. Some of the first clinical trials focused mainly on solid tumors and provided valuable data which were utilized when the drug was transitioned into hematologic malignancies. Unfortunately, efficacy of elacytarabine in solid tumors has been minimal, thereby shifting the focus of this novel therapeutic away from this group of patients. However, efficacy has been promising in hematologic malignancies, which has led to development of several clinical studies as described below.

As part of an open-label, first in man phase I clinical trial published in 2009, Dueland and colleagues studied the effect of elacytarabine in 31 patients with solid tumors (19 melanoma, 8 ovarian cancer, 7 nonsmall cell lung cancer). The objectives of this study were to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended dose, pharmacokinetic profile and tumor response. Patients received elacytarabine as a 30 minute or 2 hour intravenous (IV) infusion daily for 5 consecutive days every 3 or 4 weeks and dosing was escalated from 30 to 240 mg/m2/day using a modified Fibonacci regimen. The number of treatment cycles per patient was limited by progressive disease or unacceptable adverse events (AEs) and all patients enrolled experienced at least one treatment-related AE. In this study, most grade 3 or 4 AEs were neutropenia and the 4-week schedule was preferred due to the neutropenic nadir which occurred between days 18 and 26. MTD was 240 mg/m2/day for days 1–5 every 4 weeks and 1 patient experienced a partial response (PR) to therapy. Based on results of this study, the authors concluded that elacytarabine may have antitumor activity in solid tumors and also determined that safety and tolerability may be dependent on both dose and schedule of administration [Dueland et al. 2009].

Giles and colleagues in a phase I and pharmacokinetic study of elacytarabine determined DLT and pharmacokinetics of two single agent elacytarabine schedules in patients with refractory AML. A total of 77 patients were enrolled and received either elacytarabine administered over 4 hours at doses of >2000 mg/m2 days 1–5 over a 3 week cycle or elacytarabine administered over 24 hours at the same dose and with the same schedule. All AEs in both groups were reversible and were as expected for patients with advanced hematologic malignancies. Based on data collected in this study, recommendations were made to treat patients with elacytarabine 2000 mg/m2 daily via continuous IV infusion over days 1–5 of a 3 week cycle in phase II studies. This trial was of particular importance as older patients up to age 92 years old were treated on this protocol and did not experience any neurologic toxicity, suggesting that elacytarabine may be effective and well tolerated in older patients with AML, a group of patients for whom effective and safe therapies are lacking [Giles et al. 2012b].

In 2012, O’Brien and colleagues published an open-label, nonrandomized, multicenter phase II clinical trial to assess the efficacy and safety of elacytarabine monotherapy in patients with relapsed or refractory AML who had previously failed at least two induction regimens. A total of 61 patients were enrolled to receive elacytarabine and outcomes were compared with a group of 594 historical controls with relapsed/refractory AML [Giles et al. 2005]. Elacytarabine was administered intravenously at a dose of 2000 mg/m2 per day continuously during days 1–5 of a 3 week cycle of therapy. Remission rate was assessed after 1 or 2 cycles and survival was compared at 6 months. A total of 18% of patients achieved a complete response (CR) or a partial complete response (CRp) in the treatment group compared with 4% in historical controls. Median overall survival was 5.3 months in elacytarabine treated patients compared with 1.5 months in historical controls. A total of 51 out of 61 patients had an AE attributed by the investigator to elacytarabine and 40 patients had a grade 3 or 4 AE likely attributed to elacytarabine. The most common grade 3/4 AEs included cytopenias, febrile neutropenia, fatigue, hypokalemia and hyponetremia. This safety profile was consistent with data reported in phase I studies. Based on the aforementioned results from phase II studies, investigators concluded that elacytarabine has monotherapy activity in patients with advanced AML [O’Brien et al. 2012]. Interestingly, due to promising results early on including improved remission rates and survival, this trial was stopped early and the decision was made to proceed to phase III trial investigating elacytarabine as a single agent versus the investigator’s choice therapy in patients with advanced relapsed or refractory AML. In this trial, the CLAVELA study, patients received elacytarabine 2000 mg/m2/day by continuous infusion for 5 days or 1 of 7 investigator’s choice chemotherapy regimens. This international randomized trial enrolled 381 patients with primary endpoint being overall survival. Unfortunately, there was no significant difference in outcomes including overall survival, response rate or relapse-free survival in patients who received elacytarabine compared with investigator’s choice of therapy. There was also no difference in survival when comparing all 7 investigator’s choice chemotherapy regimens, leading investigators to conclude that no therapy regimen given as part of this trial had clinically meaningful benefit for patients with relapsed or refractory AML [Roboz et al. 2014].

In addition to utilizing elacytarabine as monotherapy, a recent phase I study by Giles and colleagues assessed the combination of elacytarabine plus idarubicin in patients with refractory AML. In this study, the proposed objectives were to determine DLT, assess the pharmacokinetics of elacytarabine in combination with iradubicin, and to establish toxicity and activity profiles of combination therapy. A total of 15 patients with refractory AML were enrolled and were treated with elacytarabine by continuous IV infusion on days 1–5 of a 3 week cycle as well as idarubicin 12 mg/m2/day on days 2–4 of a 3 week cycle. Based on DLTs, a dose of 1000 mg/m2/day was chosen as the appropriate dose. Of the patients treated with 1000 mg/m2/day dosing of elacytarabine, 4/10 patients achieved a CR or CRp, and of this group of patients, 3 had failed previous induction with cytarabine and idarubicin. Pharmacokinetic data supported efficacy of elacytarabine as plasma levels of cytarabine demonstrated longer half life after elacytarabine administration and area under the curve (AUC) values for both cytarabine and elacytarabine in plasma were documented in ranges associated with cytotoxicity or cancer cell death. This led investigators to conclude that elacytarabine allows for high levels of intracellular cytarabine as well as potentially prolonged exposure of leukemic cells to active metabolite ara-CTP. This study also suggested that expression of hENT1 may be useful in predicting response to elacytarabine therapy [Giles et al. 2012a].

Rizzieri and colleagues reported a phase II study that has assessed the combination of elacytarabine plus idarubicin as second-line induction therapy for patients with AML. This study not only assessed efficacy of combination therapy but also investigated the use of hENT1 expression as a potential biomarker or predictor of cytarabine response. A total of 51 patients who had failed initial induction chemotherapy were enrolled and were treated with combination elacytarabine 1000 mg/m2/day by continuous IV infusion for 5 days and idarubicin 12 mg/m2/day IV days 1–3 every 3 weeks as second-line therapy to induce remission. hENT1 expression was measured prior to first induction or prior to treatment with elacytarabine and was followed over time. A total of 16 patients achieved a CR and 5 achieved an incomplete CR (CRi) resulting in a 41% overall response rate. All 51 patients experienced an AE and 50 patients had a grade 3 or 4 AE, with most common events being febrile neutropenia, nausea, diarrhea, fatigue and hypokalemia. This side effect profile was consistent with profiles reported in earlier trials and was expected for patients with relapsed/refractory AML. Similar side effects would also be expected with cytarabine and are not unique to elacytarabine. Use of hENT1 as a biomarker for both cytarabine and elacytarabine response was not supported by results from this trial, although there was a trend to suggest that hENT1 expression may influence response to cytarabine based therapies [Rizzieri et al. 2014]. The authors ultimately concluded that idarubicin and elacytarabine therapy is active in patients who fail first induction for AML, although may not be superior to current standard therapy in this clinical situation.

Conclusion

Elacytarabine is a novel chemotherapeutic agent developed as a modified version of an already effective antileukemic agent, cytarabine. It is superior to standard cytarabine in some respects as it overcomes several resistance mechanisms classically associated with cytarabine including altered hENT1 expression, low intracellular levels of active cytarabine metabolites, and decreased destruction of both active and inactive metabolites. Along with bypassing resistance mechanisms, elacytarabine also has several unique mechanisms of action including inhibition of RNA synthesis. However, several resistance mechanisms such as decreased DCK expression are still problematic despite lipid modification as cytarabine, once in the cell, still requires DCK for metabolism into active ara-CTP. Preclinical and early phase data were encouraging and supported further investigation of elacytarabine as monotherapy and as part of combination therapy in phase III clinical trials. Unfortunately, elacytarabine did not show improved outcomes when used as monotherapy in AML patients with relapsed or refractory disease. There are some data to support its use in combination for patients with refractory AML, though it is not clear that elacytarabine provides additional benefit compared with current chemotherapy regimens. Data also suggested a potential role of hENT expression as a clinical correlate which may be predictive of cytarabine response. Here again, advanced prospective data to support efficacy are not as promising as we had initially hoped although further studies are certainly warranted.

Footnotes

Conflict of interest statement: The authors declare no conflict of interest in preparing this paper.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Contributor Information

Lindsay A. M. Rein, Duke University Medical Center – Medicine, Durham, NC, USA

David A. Rizzieri, Duke University Medical Center – Medicine, 1149 North Pavilion Duke University Durham, NC 27710, USA

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