Drug Evaluation
Clofarabine in the treatment of myelodysplastic syndromes Jeffrey Bryan, Hagop Kantarjian, Hillary Prescott & Elias Jabbour† 1.
Introduction
2.
Clofarabine mechanism of action
3.
Pre-clinical experience with clofarabine
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4.
Pharmacokinetics of clofarabine in humans
5.
Pharmacodynamics of clofarabine
6.
Clofarabine experience in pediatric patients
7.
Single agent clofarabine experience
8.
Oral clofarabine experience
9.
Clofarabine in combination with Ara-C
10.
Clofarabine post-hypomethylating failures
11.
Conclusion
12.
Expert opinion
The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia, Houston, TX, USA
Introduction: Clofarabine is a second-generation purine nucleoside analog approved in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia (ALL) following failure of at least two prior regimens. Clofarabine is a hybrid of fludarabine and cladribine, designed to overcome the pharmacologic limitations associated with its predecessors, while retaining their beneficial properties. In addition to providing a valuable treatment option for pediatric patients with ALL, clofarabine alone and in combination with cytarabine (Ara-C) has demonstrated substantial activity against myelodysplastic syndrome (MDS), thus rendering this agent a potential therapeutic option for MDS. Areas covered: This review focuses on the pharmacology and clinical activity of clofarabine in MDS, as well as its emerging role in the treatment of MDS. Publications in English were selected from the MEDLINE (PubMed) database, as well articles of interest from bibliographies and abstracts based on the publication of meeting materials. Expert opinion: DNA-methyltransferase inhibitors are the mainstay of therapy for many patients with MDS who require treatment. Although these agents are very well tolerated and represent a significant advancement in the treatment of MDS by improving transfusion requirements and prolonging survival in various subgroups of patients, response rates are modest and the duration of response is short. In addition to providing a valuable treatment option for pediatric ALL patients, clofarabine has substantial activity against MDS and is well tolerated by elderly patients, thus rendering it a potential therapeutic option. Keywords: clofarabine, myelodysplastic syndrome, pharmacodynamic, pharmacokinetic, purine nucleoside analogs Expert Opin. Investig. Drugs (2014) 23(2):255-263
1.
Introduction
Purine nucleoside analogs are among the most active agents in the management of hematologic malignancies. Clofarabine (2-chloro-9-[2¢-deoxy-2¢-fluoro-b-D-arabinofuranosyl]-9H-purine-6-amine; Cl-F-ara-A; CAFdA) is a second-generation purine nucleoside analog with substantial activity against acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) (Box 1) [1-3]. Clofarabine was designed to capture the favorable antimetabolic properties of cladribine and fludarabine that confer improved stability of the compound in both the plasma and an acidic environment while retaining their clinical benefit (CB). Similar to cladribine, this hybrid drug retains the 2-chloroadenine aglycone moiety which renders clofarabine resistant to intracellular degradation by adenosine deaminases. Similar to fludarabine, the introduction of fluorine at the carbon 2¢-up position of the deoxyribose moiety inhibits cleavage of the glycosidic linkage that is otherwise susceptible to enzymatic phosphorolysis by the bacterial purine nucleoside phosphorylase found in the gastrointestinal tract, resulting in improved stability of the compound in a 10.1517/13543784.2014.877887 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Clofarabine II Myelodysplastic syndrome DNA synthesis inhibitor Intravenous NH2
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N
N
N
N
CI
F O
3.
HO OH
Pivotal trial(s)
[3,27]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
gastric acidic environment and enhanced oral bioavailability [4-6]. These structural features confer other advantages as well. For instance, clofarabine has a higher affinity for deoxycytidine kinase (dCK) compared with deoxycytidine (natural nucleoside) and cladribine, as well as prolonged retention of phosphorylated clofarabine metabolites in blast cells. Clofarabine triphosphate also potently inhibits ribonucleotide reductase (RNR) and DNA polymerase more so than cladribine and fludarabine [7]. Based on the induction of complete responses, clofarabine received approval by the U.S. FDA in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL, also known as acute lymphocytic leukemia) after failure of at least two prior regimens [8]. Given its favorable toxicity profile, especially in elderly patients with AML and MDS and a potential for oral administration, clofarabine is evolving as a potential therapy for patients with MDS. 2.
Clofarabine mechanism of action
Clofarabine is a prodrug that lacks activity on its own. Clofarabine gains entry into cells via human equilibrative nucleoside transporters and passive transport across the lipid membrane at higher concentrations and longer exposure times [9]. Following entry into the cell, clofarabine is metabolized to the 5¢-monophosphate by dCK and then converted to the active 5¢-triphosphate moiety by mono- and di-phosphokinases before exerting its cytotoxic affects [9]. Clofarabine has an 256
enhanced affinity for this activating phosphorylating enzyme, dCK, equal to or exceeding that of cladribine and the natural substrate, deoxycytidine [10]. Clofarabine triphosphate depletes deoxynucleotide triphosphate pools through the inhibition of RNR and causes premature termination of DNA chain elongation through incorporation into the DNA strand and competitive inhibition of DNA polymerases [10-14]. Similar to cladribine, clofarabine has been shown to be active against non-dividing lymphocytes and disrupt the integrity of mitochondria in primary chronic lymphocytic leukemia cells resulting in the release of pro-apoptotic mitochondrial factors and programmed cell death [15]. Given these mechanisms, clofarabine is likely most active in the S-phase of the cell cycle. To further enhance its antileukemic activity, clofarabine was recently combined with cytarabine (Ara-C) and in several clinical trials for MDS.
Pre-clinical experience with clofarabine
Clofarabine was first synthesized in the 1980s by the Southern Research Institute in Birmingham, AL, USA and MD Anderson Cancer Center acquired the development rights in 1992. Delay in its development by pharmaceutical companies was most likely due to the lack of convincing evidence for its activity in non-lymphoproliferative malignancies [16]. Furthermore, the availability of other nucleoside analogs such as Ara-C, fludarabine and cladribine may have stymied its clinical development during those early years. Pre-clinical studies conducted by Kantarjian et al. in 1992 using mouse models established the lethal dose of clofarabine that kills 10% (LD10) at 75 mg/kg/day which is equivalent to 225 mg/m2 intravenously (i.v.) over 1 h daily; the dose-limiting toxicity (DLT) was gastrointestinal [16]. In canines, myelosuppression and gastrointestinal toxicities were severe at 7.5 mg/kg/day for 5 days which is equivalent to 150 mg/m2 i.v. daily for 5 days [16]. On autopsy, necrosis of the bowels was observed. For Phase I clinical trials, a dose of 15 mg/m2 daily (1/10th of LD10 in dogs) for 5 days was approved by the FDA in 1998 [16]. 4.
Pharmacokinetics of clofarabine in humans
The population pharmacokinetics (PK) of plasma clofarabine and intracellular clofarabine triphosphate has been well characterized in pediatric patients with advanced hematologic malignancies by Bonate et al. [17]. Forty pediatric patients aged 2 -- 19 years (19 females and 21 males) with relapsed or refractory ALL (n = 24) and AML (n = 16) were treated with clofarabine 52 mg/m2 i.v. daily for 5 days and PK samples were collected on days 1 and 5 with the first cycle. The PK of clofarabine fit a two-compartment model and plasma clofarabine concentrations were similar across a wide range of body surface areas [17]. Clofarabine was only 47% bound to plasma proteins, primarily albumin and the estimated volume of distribution was 172 l/m2 suggesting extensive
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Clofarabine
tissue distribution. For a 40 kg person, the estimated systemic clearance was 28.8 l/h/m2 and the primary route of elimination was renal excretion, with 57% of the dose excreted unchanged in the urine [17]. However, the pathways involved in extra-renal excretion have not been elucidated. Furthermore, the disposition of clofarabine has not been studied in patients with renal and hepatic impairment or hemodialysis. In 52 adults, patients treated once a week with clofarabine doses up to 129 mg/m2 in a Phase I study for advanced solid tumors, the average systemic clearance, volume of distribution at steady state and half-life of clofarabine were 9.9 l/h/m2, 39 l/m2 and 4 h, respectively [18,19]. The PK of oral clofarabine have also been studied in 23 adult patients with locally advanced or metastatic tumors (CLO-152 study). The mean absorption time of oral clofarabine was 1.56 h and 57% of the drug was absorbed [18].
30 mg/m2 doses [21]. By contrast, complete inhibition of DNA synthesis was maintained for 24 h at the 40 and 55 mg/m2 doses: thus, suggesting a dose-dependent effect on the maintenance inhibition of DNA synthesis by clofarabine treatment. The MTD (40 mg/m2/day) was effective with regard to inhibition of DNA synthesis and decline in circulating leukemia blasts [21]. Among the 32 evaluable patients with leukemia in this Phase I trial, two patients achieved a CR and 3 achieved a marrow CR. These promising findings defined a clofarabine dose of 40 mg/m2 daily for 5 days per course as the dose for future Phase II studies in adult leukemia.
Clofarabine experience in pediatric patients
6.
Phase I trial The first trial with clofarabine in pediatric patients with refractory or relapsed acute myeloid and lymphoblastic leukemia was conducted in 2000 [22]. Six dose levels ranging from 11.25 and 70 mg/m2/day for 5 days were tested in 25 pediatric patients with AML (n = 8) and ALL (n = 17). A majority of the patients in the study were heavily pretreated and 36% received prior allogeneic stem cell transplantation (ASCT). Since two patients treated at 70 mg/m2 i.v. daily for 5 days experienced reversible grade 3 and 4 DLTs of transaminitis and skin rash, the MTD was determined to be 52 mg/m2 i.v. daily for 5 days. Among the 13 patients treated at 52 mg/m2 for 5 days, 3 patients experienced grade 2 hyperbilirubinemia and 2 patients experienced grade 3 transaminitis, all of which resolved within a few weeks. Five patients achieved CR and three a partial response (PR) for an overall response rate (ORR) of 32%. These findings led to the recommended clofarabine dose of 52 mg/m2 i.v. over 2 h daily for 5 days for the Phase II pediatric trial. 6.1
5.
Pharmacodynamics of clofarabine
The pharmacodynamics of clofarabine was studied in 51 patients with various solid tumors (n = 13), chronic lymphoproliferative disorders (n = 6) and refractory acute leukemias (n = 32) in a Phase I study [20]. Intravenous clofarabine was administered in an escalating manner for 5 days starting at a dose of 15 mg/m2 i.v. daily for 5 days. Due to grade 4 myelosuppression observed at this dose in the indolent and solid tumor subjects, clofarabine was deescalated to 2 mg/m2/day for 5 days. The DLT subsequently was determined to be 2 and 4 mg/m2/day for 5 days for solid tumor and chronic lymphoproliferative disorders, respectively. By contrast, the dose was escalated to 55 mg/m2 for 5 days in the patients with acute leukemia before the maximum tolerated dose (MTD) of 40 mg/m2 was identified [20]. Manageable grade 3 hepatotoxicity was observed in 2 of 4 patients at the 55 mg/m2 dose level. In 26 of the 32 adults with refractory leukemia (13 ALL, 16 AML and 3 chronic myelogenous leukemia in blastic phase (CML-BP)) in the same Phase I study, the clofarabine dose was escalated from 4 to 55 mg/m2/day for 5 days as a 1 h i.v. infusion [21]. Plasma pharmacology studies revealed a linear increase in the plasma clofarabine concentration with increasing doses but a wide variation in clofarabine triphosphate concentrations [21]. At 40 mg/m2, the median plasma clofarabine concentration in 7 patients was 1.5 µM (range 0.42 -- 3.2 µM) and median concentration of the triphosphate analog was 19 µM (range 3 -- 52 µM), well above endogenous levels of deoxyadenosine triphosphate (dATP), thus, suggesting a favorable ratio (clofarabine triphosphate: dATP) for incorporation of the triphosphate analog into DNA [21]. Furthermore, the accumulation of intracellular triphosphate seemed to correlate with a decrease in DNA synthesis. At doses of 22.5 -- 55 mg/m2, DNA synthesis was 75 -- 95% inhibited at the end of the infusions but partial recovery of DNA synthesis was observed at 24 h with the 22.5 and
Phase II trial In a Phase II study, 61 heavily pretreated pediatric patients with refractory or relapsed ALL were treated with clofarabine 52 mg/m2 i.v. daily for 5 days every 2 -- 6 weeks [23]. All the patients received at least 2 prior regimens and 18 of the 61 patients (29%) had undergone prior ASCT. Thirty-five of the 61 patients (57%) were refractory to their last course of chemotherapy. Seven patients (12%) achieved a complete remission (CR), five patients (8%) achieved a CR without platelet recovery (CRp) and six patients (10%) achieved a PR for an ORR of 30%. Overall, clofarabine was well tolerated by this heavily pretreated population. The most common grade 3 or 4 adverse events were febrile neutropenia, anorexia, hypotension and nausea. Based on these results, clofarabine was approved by the FDA in 2004 for the treatment of pediatric patients with relapsed or refractory ALL after at least two prior regimens. 6.2
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7.
Single agent clofarabine experience
Based on the results from Phase I dose finding and pharmacodynamic studies, Kantarjian et al. explored single agent clofarabine in 62 patients with relapsed and refractory AML (n = 31), MDS (n = 8), ALL (n = 12) and CML-BP (n = 11) (Table 1) [1]. All patients received clofarabine at a dose of 40 mg/m2 i.v. daily for 5 days every 3 -- 6 weeks. The ORR for the group was 48% and among the 62 patients treated, 20 patients (32%) achieved a CR, 1 patient a PR and 9 patients (15%) a hematologic improvement (HI). Thirteen patients (42%) achieved a CR and 4 (13%) a CRp, for an ORR of 55%. Of note, response rates were higher in patients in first salvage and a CR duration for > 12 months. Among the six patients with MDS, two patients achieved CR and two a CRp, for an ORR of 50%. ORRs were 58 and 16% in patients with CML-BP and ALL, respectively. The duration of responses ranged from 1 to 10+ months for patients with AML and ALL and the median survival was 7 months. Frequent non-hematologic adverse events included transient liver dysfunction, rash, palmoplantar erythrodyesthesia and mucositis. Among the 62 patients, 24 patients experienced transient grade 3 or 4 hepatic dysfunction. Most patients (81%) experienced febrile neutropenia and a documented infection was present in 50% of the cases. Interestingly, pharmacodynamic studies revealed the accumulation of significantly more clofarabine triphosphate in leukemic blasts in responders compared with non-responders. 8.
Oral clofarabine experience
Oral clofarabine has demonstrated anti-tumor activity in both solid and hematological tumor xenograft mouse models [5,24-26]. Clofarabine was cytotoxic at lower IC50 levels than fludarabine in vitro against numerous human cell lines including L1210 and K562 leukemic cells [6,24]. In two Phase II trials, Faderl et al. explored the safety and efficacy i.v. and oral formulations of clofarabine in 61 patients with high-risk MDS and ‡ 5% blasts or International Prognostic Scoring System (IPSS) intermediate-2 (Int-2) and high-risk, chronic myelomonocytic leukemia (CMML) and refractory cytopenias by French American British definition (Table 1) [27]. Among the 61 patients, 6 had refractory anemia (RA), refractory anemia with ring sideroblasts or refractory cytopenia with multilineage dysplasia, 17 had refractory anemia with excess blasts-1 (RAEB-1), 16 had RAEB-2, 11 had CMML and 11 had RAEB-t. Thirty-six patients were adaptively randomized (based on response) to receive clofarabine 15 or 30 mg/m2 i.v. over 1 h daily for 5 days every 4 -- 6 weeks. In the second trial, oral clofarabine was tested in 25 patients. The starting dose was 40 mg/m2 orally daily for 5 days every 4 -- 6 weeks, which was subsequently decreased to 30 mg/m2 orally daily for 5 days after 6 patients had been treated on the higher dose. Overall, 42 patients had advanced disease or poor risk 258
disease: 69% had high or Int-2 risk disease by IPSS and approximately 33% of the patients had secondary MDS. A substantial proportion of patients (64%) had failed prior therapy with either decitabine or azacitidine. A combined ORR of 47% was gained (50% with oral clofarabine, 37 -- 50% with i.v. clofarabine). A combined CR rate of 30% was obtained (29% with oral clofarabine, 25 -- 35% with i.v. clofarabine). Three patients (13%) in the oral clofarabine arm gained a HI. Common non-hematologic adverse events were nausea, vomiting, skin rash, hyperbilirubinemia and transaminase elevations. As expected in this population, myelosuppression and hospitalizations for neutropenic fever were common. Grade 3 or higher adverse events rarely occurred. Faderl et al. explored the safety and tolerability of the oral formulation of clofarabine in 32 patients with higher-risk MDS based on WHO criteria with marrow blasts ‡ 5% or IPSS intermediate or high-risk group and patients with CMML [28]. Twenty-two patients had Int-2 or high-risk by IPSS. By WHO criteria, two-thirds (68%) of the patients were diagnosed with RAEB-1 or 2. Nine patients had secondary MDS and 20 patients failed prior therapy with hypomethylating agents (HMAs). In this trial, three dose levels of oral clofarabine were explored: 20, 30 and 40 mg/m2 daily for 5 days every 4 -- 8 weeks. CR was defined as normalization of blood with neutrophils ‡ 1 109/l and a platelets ‡ 100 109/l with ‡ 5% marrow blasts and HI was defined as meeting all criteria for CR except for platelet recovery [28]. CB was defined according to the following criteria: increase of platelets by 50% and to > 30 109/l, neutrophil increase by 100% and to > 1 109/, hemoglobin increase by 2 g/dl and/or transfusion independence [28]. The ORR was 43% with eight patients achieving a CR (25%) and three patients each attained an HI (9%) and CB (9%). In those who failed HMAs, the ORR was lower at 30%; two patients achieved a CR (10%), two a HI (10%) and two a CB (10%). Additional trials are planned to define the optimal dose and schedule of i.v. and oral clofarabine in MDS.
9.
Clofarabine in combination with Ara-C
A number of biomodulating strategies have been explored to exploit the activity of Ara-C in myeloid blast cells, by increasing intracellular concentrations of Ara-C triphosphate (AraCTP), resulting in synergistic killing of myeloid leukemia cells [29-32]. These efforts have been tested and validated clinically using combinations of Ara-C with fludarabine and cladribine in adult and pediatric AML [33]. Another interesting approach involved incubation of K562 cells with clofarabine followed 3 h later by Ara-C that caused nearly a threefold increase of intracellular Ara-CTP levels relative to cells that were incubated with Ara-C alone [11,32]. Based on these compelling findings, Faderl et al. tested the clofarabine and Ara-C combination in a Phase I/II study in 32 patients with advanced acute leukemia (25 AML, 2 ALL, 4 with high-risk
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Clofarabine
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Table 1. Activity of clofarabine in higher-risk MDS responses. Study
Phase
Population
Faderl et al. [28]
II
MDS
Faderl et al. [28] Kantarjian et al. [1]
II II
Faderl et al. [35]
II
Nazha et al. [40]*
II
MDS R/R AML MDS CML-BP R/R ALL Newly diagnosed AML and MDS Post-HMA failure
Induction strategy
CLO CLO CLO CLO CLO
30/40 mg/m2/d p.o. 5-d 15 mg/m2/d i.v. 5-d 30 mg/m2/d i.v. 5-d 20/30/40 mg/m2/d p.o. 5-d 40 mg/m2/d i.v. 5-d
CLO 40 mg/m2/d i.v. 5-d followed by Ara-C 1000 mg/m2/d i.v. 5-d CLO 15 mg/mg2/d i.v. 5-d with Ara-C 20 mg s.c. b.i.d. for 7-d
N
CR no. (%)
CRi no. (%)
Overall no. (%)
24 20 16 32 31 8 11 12 60
7 (29) 7 (35) 4 (25) 8 (25) 13 (42) 2 (25) 4 (36) 1 (8) 31 (52)
2 (8) 3 (15) 2 (13) -4 (13) 2 (25) 1/2 (27) 1 (8) 5 (8)
9 (38) 10 (50) 6 (38) 8 (25) 17 (55) 4 (50) 7 (64) 2 (17) 36 (60)
24
8 (33)*
NR
12 (50)z
*CR includes patients with a CR, CRi, marrow CR. z The ORR includes four patients with an HI not shown in the table. AML: Acute myelogenous leukemia; Ara-C: Cytarabine; CLO: Clofarabine; CML-BP: Chronic myelogenous leukemia blast phase; CR: Complete remission; CRi: CR without complete recovery of counts; HI: Hematologic improvement; HMA: Hypomethylating agent; i.v.: Intravenous; MDS: Myelodysplastic syndrome; N: Number treated; NR: Not reported; p.o.: Oral; R/R: Relapsed or refractory; s.c.: Subcutaneous.
MDS defined by more than or equal to 10% blood or marrow blasts and 1 CML-BP) [34]. Clofarabine was administered at escalating doses of 15 -- 40 mg/m2 i.v. daily for 5 days (days 2 -- 6) followed 4 h later by Ara-C 1000 mg/m2 i.v. over 2 h daily for 5 days (days 1 -- 5). The dose of clofarabine in the Phase II part was 40 mg/m2 i.v. daily for 5 days. The ORR in AML was 40% (28% CR, 12% CRp). Two of the four patients (50%) with MDS achieved a CRp (CR without recovery of platelets) and none of the patients with ALL and CML responded to therapy. The median duration of remission was 3.2 months and the median overall survival (OS) was 5.5 months. Those who achieved a CR or CRp had a median survival of 7.9 months. The adverse events observed in this trial were mainly grade 2 and consisted of transient liver test abnormalities, nausea and vomiting, diarrhea, skin rashes including hand-foot syndrome and mucositis. In another Phase II trial, Faderl et al. evaluated the efficacy of clofarabine in combination with Ara-C as frontline therapy in 60 older adults (median age of 61 years) with AML or high-risk MDS (‡ 10% marrow blasts) [35]. Clofarabine was given at 40 mg/m2/day over 1 h i.v. daily for 5 days (days 2 -- 6) followed 4 h later by Ara-C at 1000 mg/m2 over 2 h i.v. daily for 5 days (days 1 -- 5). Among the 60 patients enrolled, 53 patients had AML and 8 had high-risk MDS. Overall, 36 patients (60%) responded, 31 patients (52%) achieved CR and 5 patients (8%) a CRp. Nine patients (15%) died while on study. The CR rate with this regimen is in line with the CR rates observed with other induction regimens in elderly patients with AML. Clofarabine alone or in combination with low-dose Ara-C were evaluated in 70 elderly patients (median age of 71) with previously untreated AML or high-risk MDS by WHO criteria (2 = REAB-2, 1 = CMML-1, 1 = CMML-2) [2]. The
patients were adaptively randomized to clofarabine (30 mg/m2 i.v. daily for 5 days) with or without low-dose Ara-C (20 mg/m2 subcutaneous (s.c.) daily for 14 days). Sixteen patients received single agent clofarabine and 54 patients received combination therapy. The overall CR rate was 56% and the CR rate was significantly higher with the combination (63 vs 31%; p = 0.025). Although not statistically significant, the induction mortality was lower with the combination versus clofarabine alone, 19 vs 31% (p = 0.276), respectively. The combination also demonstrated better event-free survival (7.1 vs 1.7 months; p = 0.04), but an OS benefit was not observed (11.4 vs 5.8 months; p = 0.1). More recently, Burnett et al. randomized 406 older patients (median age 74 years) with de novo AML (62%), secondary AML (24%) and high-risk MDS (15%) (10% marrow blasts) to one of two arms: clofarabine 20 mg/m2 i.v. daily for 5 days or low-dose Ara-C (LDAC)20 mg s.c. twice daily for 10 days every 6 weeks with the aim of delivering 4 courses of therapy (Table 2) [3]. The median number of courses for each group was 2. Among the 29 high-risk MDS patients in the clofarabine arm, 12 (41%) achieved a CR, whereas 6 of the 30 (20%) in the Ara-C arm achieved a CR. An overall remission rate (CR + CRi (CR without recovery of counts)) was achieved in 28% of the patients and the 2-year survival was 13%. Clofarabine significantly improved CR (22 vs 12%; hazard ratio [HR] = 0.47 [0.28 -- 0.79]; p = 0.005) and overall response (38 vs 19%; HR = 0.41 [0.26 -- 0.62]; p < 0.0001), but there was no difference in OS, explained by poorer survival in the clofarabine patients who did not gain CR (3 for clofarabine vs 4% LDAC; p = 0.02) and following relapse (0 for clofarabine vs 8% LDAC; p = 0.02) [3]. Additionally, there was no difference between the 2 arms for relapse-free survival at 2 years (20 for clofarabine vs 8% for LDAC; p = 0.2) or 2 years survival from CR (26 vs 44%; p = 0.5).
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Table 2. Clofarbine-based randomized trials in MDS. Study
Population
Induction Strategy
N
Faderl et al. [2]
Newly Dx older AML, MDS
CLO 30 mg/m2/d i.v. 5-d vs CLO + 20 mg s.c. Ara-C daily 14-d CLO 20 mg/m2/d i.v. 5-d vs Ara-C 20 mg s.c. BID 10-d
16 54
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Burnett et al. [3] Newly Dx older AML, MDS
CR no. (%) 5 (31) 34 (63)
ORR no. (%) 5 (31) 36 (67)
OS mo.
Comments
5.8 11.4
Induction mortality (31% vs 19%; p = 0.276) EFS (7.1 mo. vs 1.7 mo; p = 0.04) (p = 0.025) (p = 0.012) (p = 0.1) No OS benefit 200 44 (22) 75 (38) 11.4 MDS ORR (41% vs 20%) 206 25 (12) 40 (19) 12 Induction mortality (18% vs 12%; p = 0.2) 2-y survival nonCR (3% vs 4%; p = 0.02) (p = 0.005) (p = 0.0001) (p = 0.7) No OS benefit
AML: Acute myelogenous leukemia; Ara-C: Cytarabine; BID: Twice daily; CLO: Clofarabine; CR: Complete remission; CRi: CR without complete recovery of counts; Dx: Diagnosed; EFS: Event free survival; HMA: Hypomethylating agent; HR; Higher-risk; i.v: Intravenous; N: Number treated; ORR: Overall response rate; OS: Overall Survival; po: Oral; s.c: Subcutaneous.
Thus, suggesting this difficult-to-treat population may not require a CR for improved survival. Those who received clofarabine required significantly more support for increased myelosuppression and experienced significantly higher rates of manageable grade 3 or higher gastrointestinal and hepatic toxicity. 10.
Clofarabine post-hypomethylating failures
The prognosis for patients failing DNA HMAs is poor and therapeutic options available are limited [36-38]. Given the promising activity of clofarabine shown in prior studies in patients with AML and MDS, Lim et al. embarked on a Phase II study that evaluated the safety and efficacy of low-dose clofarabine in patients with MDS who failed prior therapy with 5-azacitidine. In this study, 10 patients with MDS of any risk group by WHO criteria, who failed to respond to 5-azacytidine after at least six cycles therapy or whose MDS progressed while on 5-azacytidine, were enrolled [39]. By WHO classification, six patients were RA, two RAEB-1, one RAEB-2 and one AML and four patients (40%) harbored poor cytogenetics. The median age of the group was 73 years (range 65 -- 78 years). Two cohorts of patients were treated with clofarabine every 4 -- 8 weeks until disease progression or intolerable toxicities. Eight patients in the first cohort were treated with intravenous clofarabine at 10 mg/m2/day (25% of standard dose) for 5 consecutive days. Since profound hematologic toxicities were observed in the patients in cohort 1, the second cohort of patients (cohort 2) received a reduced dose of intravenous clofarabine at 5 mg/m2/day for 5 days instead of the planned 15 mg/m2/day. Of note, all patients received pegfilgrastim 6 mg on day 5 of each cycle of clofarabine. A median of two cycles (range 1 -- 4) were administered. Among the nine patients evaluable for response, one patient achieved a CR, one a PR and 2 a HI for an ORR of 44%. An ORR of 67% (4/6 patients) was observed in patients with low-risk MDS by IPSS. With a median follow-up of 9 months (range 0.5 -- 23 months), the OS for the group was 50% at 12 months. 260
The median duration of response was 10 months (range 6.5 -- 15.5 months). Despite the lower-than-usual dose of clofarabine used in other studies, severe and prolonged pancytopenia occurred in all 10 patients [39]. One patient who had a history of thrombocytopenic gastrointestinal bleed died due to an intracranial bleed despite aggressive platelet support. The authors concluded that low-dose clofarabine may induce response, but with significant toxicities in patients with lowrisk MDS who fail 5-azacytidine [39]. Nazha et al. have further explored the safety and efficacy of the combination of clofarabine and LDAC in the treatment of patients with high-risk MDS who failed prior hypomethylating therapy [40]. Among the 29 patients enrolled in this study, 14 were classified as RAEB, 11 RAEB-T and 4 CMML, or by IPSS, 27 patients (93%) were classified as Int-2 or high-risk MDS. Induction therapy consisted of clofarabine 15 mg/mg2 i.v. daily for 5 days (days 1 -- 5) and Ara-C 20 mg s.c. twice daily for 7 days (days 1 -- 7). Depending on tolerability and stability of disease, a maximum of three induction cycles were allowed. Responding patients received consolidation therapy with clofarabine 15 mg/mg/m2 i.v. daily for 3 days (days 1 -- 3) and Ara-C 20 mg s.c. twice daily for 5 days (days 1 -- 5) every 4 -- 8 weeks depending on hematopoietic recovery and resolution of toxicities for a maximum of 12 cycles. Among the 24 patients evaluable for response, 8 patients (33%) achieved a CR, CRp or marrow CR and 4 (17%) HI, for an ORR of 50%. With a median follow-up of 4.9 months (range 1.9 -- 16.7 months), the median OS was 4.8 months (range 0.5 -- 13.5 months) and the 4-week mortality was 12% [41]. Common non-hematologic adverse events were nausea (31%), headache (24%), rash (28%), elevated liver enzymes (41%) and febrile neutropenia (28%). Grade 3 or higher adverse events included elevated liver enzymes (3%) and elevated bilirubin (3%). Although the response rates are promising, the role clofarabine in MDS post-hypomethylating failure is questionable.
Expert Opin. Investig. Drugs (2014) 23(2)
Clofarabine
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11.
Conclusion
Clofarabine encompasses structural features of fludarabine and cladribine that contribute to improved stability of clofarabine while retaining their beneficial properties. These interesting properties of clofarabine, as well as the need to develop new therapies for adult patients with MDS, explain the increased interest in this agent over the past decade. In addition to providing an important treatment option for pediatric patients with ALL, clofarabine also has demonstrated significant ORRs in AML and MDS. The most common clofarabinerelated adverse events observed in the treatment of AML and MDS were bone marrow suppression, nausea, vomiting, diarrhea, tachycardia, fever, fatigue, transient liver dysfunction, skin rashes, palmoplantar erythrodysesthesia and mucositis. Despite the progress in MDS, there is a major need for more effective and tolerable treatments for all adults with MDS. Further studies are needed to determine the role of clofarabine in the treatment of MDS. 12.
Expert opinion
DNA-methyltransferase inhibitors are standard of care for many patients with MDS who require treatment. Although these agents represent a significant advancement in the treatment for MDS by improving transfusion requirements and prolonging survival (azacitdine) in various subgroups of patients, response rates are modest (ORRs of 28 -- 48% with CR rates 6 -- 34%) and the duration of response is < 1 year. Furthermore, failure to respond to or relapse from treatment with HMAs carries a poor outcome and no approved therapy for these patients exists [36-38]. At this time, allogeneic stem Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 2003;102:2379-86 Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 2008;112:1638-45 Burnett AK, Russell NH, Hunter AE, et al. Clofarabine doubles the response rate in older patients with acute myeloid
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cell transplant provides the only opportunity for cure. Extensive efforts are being made to improve outcomes for patients with MDS. Clofarabine is a novel second-generation purine nucleoside analog that has demonstrated significant antitumor activity in pediatric acute leukemia. As a result, it gained approval by the FDA in 2004 for the treatment of pediatric relapsed or refractory ALL. In addition to providing a valuable treatment option for pediatric patients with ALL, clofarabine alone and in combination with Ara-C also has demonstrated substantial activity against MDS and AML in the older population. Clofarabine can be used as a bridge to transplantation in patients with MDS [41]. The role of clofarabine in MDS will be to improve outcomes by increasing the response rate and decreasing the treatment-related mortality in these patients. The pharmacologic properties of clofarabine have made of it an excellent drug to be used in combination chemotherapy regimens. Its favorable toxicity profile compared with more intensive regimens makes this agent potentially useful for elderly patients, as well. Although few studies have been done in MDS alone, promising results have been achieved with single agent clofarabine in higherrisk MDS. Nevertheless, clofarabine alone is unlikely to improve long-term survival, thus supporting the rationale to seek an effective combination regimen. Furthermore, more clinical trials are necessary to better define the subgroups of patients who would benefit from this novel drug.
Declaration of interest The authors declare no conflict of interest and have received no payment in the preparation of this manuscript.
leukemia but does not improve survival. Blood 2013;122:1384-94 This randomized trial showed no OS advantage with clofarabine compared with low-dose cytarabine in elderly AML and high-risk MDS patients not suitable for intensive therapy. Parker WB, Allan PW, Hassan AE, et al. Antitumor activity of 2-fluoro-2deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase. Cancer Gene Ther 2003;10:23-9 Carson DA, Wasson DB, Esparza LM, et al. Oral antilymphocyte activity and induction of apoptosis by 2-chloro 2-arabino-fluoro-2 deoxyadenosine. Proc Natl Acad Sci USA 1992;89:2970-4 Lotfi K, Mansson E, Spasokoukotskaja T, et al. Biochemical pharmacology and resistance to 2-chloro2’-arabino-fluoro-2’deoxyadenosine, a Expert Opin. Investig. Drugs (2014) 23(2)
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novel analogue of cladribine in human leukemic cells. Clin Cancer Res 1999;5:2438-44 This article provides a good description of the pharmacologic properties of clofarabine. Xie C, Plunkett W. Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoroD-arabinofuranosyl) adenine in human lymphoblastoid cells. Cancer Res 1995;55:2847-52 This article provides a good review of the mechanism of action of clofarabine.
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Pui CH, Jeha S. Clofarabine. Nat Rev Drug Discov Suppl 2005;4:S12-S3
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King KM, Damaraju VL, Vickers MF, et al. A comparison of the transportability, and its role in cytotoxicity, of clofarabine, cladribine, and fludarabine by recombinant human nucleoside transporters produced in three model expression systems. Mol Pharmacol 2006;69:34-53 Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-(2deoxy-fluoro-beta-D-arabinofuranosyl) adenine. Cancer Res 1996;56:3030-7 Parker WB, Shaddix SC, Chang CH, et al. Effects of 2-chloro-9-(2-deoxy-2-fluorobeta-D-arabinofuranosyl) adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by 5’-triphosphate. Cancer Res 1991;51:2386-94 Parker WB, Shaddix SC, Rose L, et al. Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2fluoro-beta-D-arabinofuranosyl) adenine, 2-chloro-9-(2-deoxy-2-fluoro-betaD-arabinofuranosyl) adenine, 2-chloro-9(2-deoxy-2, 2-difluoro-beta-Dribofuranosyl) adenine in CEM cells. Mol Pharmacol 1999;55:515-20 Parker WB, Bapat AR, Shen JX, et al. Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. Mol Pharmacol 1988;34:485-91
Kantarjian HM, Jeha S, Gandhi V, et al. Clofarabine: past, present, and future. Leuk Lymphoma 2007;48:1922-30
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Bonate PL, Cunningham CC, Gaynon P. Population pharmacokinetics of clofarabine and its metabolite 6ketoclofarabine in adult and pediatric patients with cancer. Clin Cancer Res 2003;9:6335-42
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Cunningham C, Nemunaitis J, Senzer N, et al. Effect of clofarabine on lymphocyte populations in patients treated for solid tumors. J Clin Oncol 2007;25:abstract 21134
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Zhenchuk A, Lotfi K, Juliusson G, et al. Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol 2009;78:1351-9 Kantarjian H, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine (CI-F-ara-A; 2 chloro-2-fluoro-deoxy-9beta-D-arabinofuranosyladenine) in patients with solid and hematologic cancers. J Clin Oncol 2003;21: 1167-73 Gandhi V, Kantarjian H, Faderl S, et al. Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias. Clin Cancer Res 2003;9:6335-42 Jeha S, Gandhi V, Chan K, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004;103:784-9 This was the first pediatric trial of clofarabine in advanced hematological malignancies. Jeha S, Gaynon P, Razzouk B, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006;24:1917-23 This trial led to the US FDA approval of clofarabine for the treatment of pediatric patients with relapsed or refractory ALL after at least two prior regimens. Takahashi T, Kanaqawa J, Akinaga S, et al. Antitumor activity of 2-chloro-9(2-deoxy-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog m against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol 1999;43:233-40 Waud WR, Schmid SM, Montgomery JA, et al. Preclinical antitumor activity of 2-chloro-9-(2deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine (Cl-F-ara-A). Nucleosides Nucleotides Nucleic Acids 2000;19:447-60
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Avramis VI, Plunkett W. Metabolism of 9-, 6-D-arabinosyl-2fluoroadenine-41phosphate by mice bearing P388 leukemia. Cancer Drug Deliv 1983;1:1-10
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for patients with myelodysplastic syndrome. Blood 2008;112:abstract 222 First reports demonstrating activity of intravenous and oral clofarabine in MDS patients.
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Faderl S, Gandhi V, Verstovsek S, et al. Clofarabine plus cytarabine combination is active in newly diagnosed patients ‡ age 50 with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Blood 2004;104:abstract 875 This was the first study to show considerable activity of frontline therapy with clofarabine in AML and high-risk MDS.
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Jabbour E, Garcia-Manero G, Xiao L, et al. Outcome of patients (pts) with low and intermediate-1 risk myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure. Blood 2013;122:abstract 388 Lim SH, McMahan J, Zhang J, et al. A phase II study of low dose intravenous clofarabine for elderly patients with myelodysplastic syndrome who have failed 5-azacytidine. Leuk Lymphoma 2010;51(12):2258-61
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Nazha A, Garcia-Manero G, Kantarjian HM, et al. Clofarabine plus low-dose cytarabine for the treatment of patients with higher-risk myelodysplastic syndrome (MDS) who have been relapsing after, or are refractory to, hypomethylator agent therapy. Blood 2013;122:abstract 1525 Locke F, Agarwal R, Kunnavakkam R, et al. A novel clofarabine bridge strategy facilitates allogeneic transplantation in patients with relapsed/refractory leukemia and high-
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risk myelodysplastic syndromes. Bone Marrow Transplant 2013;17:1-7
Affiliation Jeffrey Bryan, Hagop Kantarjian, Hillary Prescott & Elias Jabbour† MD † Author for correspondence The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd. Box 428. Houston, TX 77030, USA Tel: +1 713 792 4764; Fax: +1 713 794 4297; E-mail: [email protected]
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Clofarabine in the treatment of myelodysplastic syndromes Jeffrey Bryan, Hagop Kantarjian, Hillary Prescott & Elias Jabbour† 1.
Introduction
2.
Clofarabine mechanism of action
3.
Pre-clinical experience with clofarabine
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4.
Pharmacokinetics of clofarabine in humans
5.
Pharmacodynamics of clofarabine
6.
Clofarabine experience in pediatric patients
7.
Single agent clofarabine experience
8.
Oral clofarabine experience
9.
Clofarabine in combination with Ara-C
10.
Clofarabine post-hypomethylating failures
11.
Conclusion
12.
Expert opinion
The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia, Houston, TX, USA
Introduction: Clofarabine is a second-generation purine nucleoside analog approved in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia (ALL) following failure of at least two prior regimens. Clofarabine is a hybrid of fludarabine and cladribine, designed to overcome the pharmacologic limitations associated with its predecessors, while retaining their beneficial properties. In addition to providing a valuable treatment option for pediatric patients with ALL, clofarabine alone and in combination with cytarabine (Ara-C) has demonstrated substantial activity against myelodysplastic syndrome (MDS), thus rendering this agent a potential therapeutic option for MDS. Areas covered: This review focuses on the pharmacology and clinical activity of clofarabine in MDS, as well as its emerging role in the treatment of MDS. Publications in English were selected from the MEDLINE (PubMed) database, as well articles of interest from bibliographies and abstracts based on the publication of meeting materials. Expert opinion: DNA-methyltransferase inhibitors are the mainstay of therapy for many patients with MDS who require treatment. Although these agents are very well tolerated and represent a significant advancement in the treatment of MDS by improving transfusion requirements and prolonging survival in various subgroups of patients, response rates are modest and the duration of response is short. In addition to providing a valuable treatment option for pediatric ALL patients, clofarabine has substantial activity against MDS and is well tolerated by elderly patients, thus rendering it a potential therapeutic option. Keywords: clofarabine, myelodysplastic syndrome, pharmacodynamic, pharmacokinetic, purine nucleoside analogs Expert Opin. Investig. Drugs (2014) 23(2):255-263
1.
Introduction
Purine nucleoside analogs are among the most active agents in the management of hematologic malignancies. Clofarabine (2-chloro-9-[2¢-deoxy-2¢-fluoro-b-D-arabinofuranosyl]-9H-purine-6-amine; Cl-F-ara-A; CAFdA) is a second-generation purine nucleoside analog with substantial activity against acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) (Box 1) [1-3]. Clofarabine was designed to capture the favorable antimetabolic properties of cladribine and fludarabine that confer improved stability of the compound in both the plasma and an acidic environment while retaining their clinical benefit (CB). Similar to cladribine, this hybrid drug retains the 2-chloroadenine aglycone moiety which renders clofarabine resistant to intracellular degradation by adenosine deaminases. Similar to fludarabine, the introduction of fluorine at the carbon 2¢-up position of the deoxyribose moiety inhibits cleavage of the glycosidic linkage that is otherwise susceptible to enzymatic phosphorolysis by the bacterial purine nucleoside phosphorylase found in the gastrointestinal tract, resulting in improved stability of the compound in a 10.1517/13543784.2014.877887 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
Clofarabine II Myelodysplastic syndrome DNA synthesis inhibitor Intravenous NH2
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N
N
N
N
CI
F O
3.
HO OH
Pivotal trial(s)
[3,27]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
gastric acidic environment and enhanced oral bioavailability [4-6]. These structural features confer other advantages as well. For instance, clofarabine has a higher affinity for deoxycytidine kinase (dCK) compared with deoxycytidine (natural nucleoside) and cladribine, as well as prolonged retention of phosphorylated clofarabine metabolites in blast cells. Clofarabine triphosphate also potently inhibits ribonucleotide reductase (RNR) and DNA polymerase more so than cladribine and fludarabine [7]. Based on the induction of complete responses, clofarabine received approval by the U.S. FDA in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL, also known as acute lymphocytic leukemia) after failure of at least two prior regimens [8]. Given its favorable toxicity profile, especially in elderly patients with AML and MDS and a potential for oral administration, clofarabine is evolving as a potential therapy for patients with MDS. 2.
Clofarabine mechanism of action
Clofarabine is a prodrug that lacks activity on its own. Clofarabine gains entry into cells via human equilibrative nucleoside transporters and passive transport across the lipid membrane at higher concentrations and longer exposure times [9]. Following entry into the cell, clofarabine is metabolized to the 5¢-monophosphate by dCK and then converted to the active 5¢-triphosphate moiety by mono- and di-phosphokinases before exerting its cytotoxic affects [9]. Clofarabine has an 256
enhanced affinity for this activating phosphorylating enzyme, dCK, equal to or exceeding that of cladribine and the natural substrate, deoxycytidine [10]. Clofarabine triphosphate depletes deoxynucleotide triphosphate pools through the inhibition of RNR and causes premature termination of DNA chain elongation through incorporation into the DNA strand and competitive inhibition of DNA polymerases [10-14]. Similar to cladribine, clofarabine has been shown to be active against non-dividing lymphocytes and disrupt the integrity of mitochondria in primary chronic lymphocytic leukemia cells resulting in the release of pro-apoptotic mitochondrial factors and programmed cell death [15]. Given these mechanisms, clofarabine is likely most active in the S-phase of the cell cycle. To further enhance its antileukemic activity, clofarabine was recently combined with cytarabine (Ara-C) and in several clinical trials for MDS.
Pre-clinical experience with clofarabine
Clofarabine was first synthesized in the 1980s by the Southern Research Institute in Birmingham, AL, USA and MD Anderson Cancer Center acquired the development rights in 1992. Delay in its development by pharmaceutical companies was most likely due to the lack of convincing evidence for its activity in non-lymphoproliferative malignancies [16]. Furthermore, the availability of other nucleoside analogs such as Ara-C, fludarabine and cladribine may have stymied its clinical development during those early years. Pre-clinical studies conducted by Kantarjian et al. in 1992 using mouse models established the lethal dose of clofarabine that kills 10% (LD10) at 75 mg/kg/day which is equivalent to 225 mg/m2 intravenously (i.v.) over 1 h daily; the dose-limiting toxicity (DLT) was gastrointestinal [16]. In canines, myelosuppression and gastrointestinal toxicities were severe at 7.5 mg/kg/day for 5 days which is equivalent to 150 mg/m2 i.v. daily for 5 days [16]. On autopsy, necrosis of the bowels was observed. For Phase I clinical trials, a dose of 15 mg/m2 daily (1/10th of LD10 in dogs) for 5 days was approved by the FDA in 1998 [16]. 4.
Pharmacokinetics of clofarabine in humans
The population pharmacokinetics (PK) of plasma clofarabine and intracellular clofarabine triphosphate has been well characterized in pediatric patients with advanced hematologic malignancies by Bonate et al. [17]. Forty pediatric patients aged 2 -- 19 years (19 females and 21 males) with relapsed or refractory ALL (n = 24) and AML (n = 16) were treated with clofarabine 52 mg/m2 i.v. daily for 5 days and PK samples were collected on days 1 and 5 with the first cycle. The PK of clofarabine fit a two-compartment model and plasma clofarabine concentrations were similar across a wide range of body surface areas [17]. Clofarabine was only 47% bound to plasma proteins, primarily albumin and the estimated volume of distribution was 172 l/m2 suggesting extensive
Expert Opin. Investig. Drugs (2014) 23(2)
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Clofarabine
tissue distribution. For a 40 kg person, the estimated systemic clearance was 28.8 l/h/m2 and the primary route of elimination was renal excretion, with 57% of the dose excreted unchanged in the urine [17]. However, the pathways involved in extra-renal excretion have not been elucidated. Furthermore, the disposition of clofarabine has not been studied in patients with renal and hepatic impairment or hemodialysis. In 52 adults, patients treated once a week with clofarabine doses up to 129 mg/m2 in a Phase I study for advanced solid tumors, the average systemic clearance, volume of distribution at steady state and half-life of clofarabine were 9.9 l/h/m2, 39 l/m2 and 4 h, respectively [18,19]. The PK of oral clofarabine have also been studied in 23 adult patients with locally advanced or metastatic tumors (CLO-152 study). The mean absorption time of oral clofarabine was 1.56 h and 57% of the drug was absorbed [18].
30 mg/m2 doses [21]. By contrast, complete inhibition of DNA synthesis was maintained for 24 h at the 40 and 55 mg/m2 doses: thus, suggesting a dose-dependent effect on the maintenance inhibition of DNA synthesis by clofarabine treatment. The MTD (40 mg/m2/day) was effective with regard to inhibition of DNA synthesis and decline in circulating leukemia blasts [21]. Among the 32 evaluable patients with leukemia in this Phase I trial, two patients achieved a CR and 3 achieved a marrow CR. These promising findings defined a clofarabine dose of 40 mg/m2 daily for 5 days per course as the dose for future Phase II studies in adult leukemia.
Clofarabine experience in pediatric patients
6.
Phase I trial The first trial with clofarabine in pediatric patients with refractory or relapsed acute myeloid and lymphoblastic leukemia was conducted in 2000 [22]. Six dose levels ranging from 11.25 and 70 mg/m2/day for 5 days were tested in 25 pediatric patients with AML (n = 8) and ALL (n = 17). A majority of the patients in the study were heavily pretreated and 36% received prior allogeneic stem cell transplantation (ASCT). Since two patients treated at 70 mg/m2 i.v. daily for 5 days experienced reversible grade 3 and 4 DLTs of transaminitis and skin rash, the MTD was determined to be 52 mg/m2 i.v. daily for 5 days. Among the 13 patients treated at 52 mg/m2 for 5 days, 3 patients experienced grade 2 hyperbilirubinemia and 2 patients experienced grade 3 transaminitis, all of which resolved within a few weeks. Five patients achieved CR and three a partial response (PR) for an overall response rate (ORR) of 32%. These findings led to the recommended clofarabine dose of 52 mg/m2 i.v. over 2 h daily for 5 days for the Phase II pediatric trial. 6.1
5.
Pharmacodynamics of clofarabine
The pharmacodynamics of clofarabine was studied in 51 patients with various solid tumors (n = 13), chronic lymphoproliferative disorders (n = 6) and refractory acute leukemias (n = 32) in a Phase I study [20]. Intravenous clofarabine was administered in an escalating manner for 5 days starting at a dose of 15 mg/m2 i.v. daily for 5 days. Due to grade 4 myelosuppression observed at this dose in the indolent and solid tumor subjects, clofarabine was deescalated to 2 mg/m2/day for 5 days. The DLT subsequently was determined to be 2 and 4 mg/m2/day for 5 days for solid tumor and chronic lymphoproliferative disorders, respectively. By contrast, the dose was escalated to 55 mg/m2 for 5 days in the patients with acute leukemia before the maximum tolerated dose (MTD) of 40 mg/m2 was identified [20]. Manageable grade 3 hepatotoxicity was observed in 2 of 4 patients at the 55 mg/m2 dose level. In 26 of the 32 adults with refractory leukemia (13 ALL, 16 AML and 3 chronic myelogenous leukemia in blastic phase (CML-BP)) in the same Phase I study, the clofarabine dose was escalated from 4 to 55 mg/m2/day for 5 days as a 1 h i.v. infusion [21]. Plasma pharmacology studies revealed a linear increase in the plasma clofarabine concentration with increasing doses but a wide variation in clofarabine triphosphate concentrations [21]. At 40 mg/m2, the median plasma clofarabine concentration in 7 patients was 1.5 µM (range 0.42 -- 3.2 µM) and median concentration of the triphosphate analog was 19 µM (range 3 -- 52 µM), well above endogenous levels of deoxyadenosine triphosphate (dATP), thus, suggesting a favorable ratio (clofarabine triphosphate: dATP) for incorporation of the triphosphate analog into DNA [21]. Furthermore, the accumulation of intracellular triphosphate seemed to correlate with a decrease in DNA synthesis. At doses of 22.5 -- 55 mg/m2, DNA synthesis was 75 -- 95% inhibited at the end of the infusions but partial recovery of DNA synthesis was observed at 24 h with the 22.5 and
Phase II trial In a Phase II study, 61 heavily pretreated pediatric patients with refractory or relapsed ALL were treated with clofarabine 52 mg/m2 i.v. daily for 5 days every 2 -- 6 weeks [23]. All the patients received at least 2 prior regimens and 18 of the 61 patients (29%) had undergone prior ASCT. Thirty-five of the 61 patients (57%) were refractory to their last course of chemotherapy. Seven patients (12%) achieved a complete remission (CR), five patients (8%) achieved a CR without platelet recovery (CRp) and six patients (10%) achieved a PR for an ORR of 30%. Overall, clofarabine was well tolerated by this heavily pretreated population. The most common grade 3 or 4 adverse events were febrile neutropenia, anorexia, hypotension and nausea. Based on these results, clofarabine was approved by the FDA in 2004 for the treatment of pediatric patients with relapsed or refractory ALL after at least two prior regimens. 6.2
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7.
Single agent clofarabine experience
Based on the results from Phase I dose finding and pharmacodynamic studies, Kantarjian et al. explored single agent clofarabine in 62 patients with relapsed and refractory AML (n = 31), MDS (n = 8), ALL (n = 12) and CML-BP (n = 11) (Table 1) [1]. All patients received clofarabine at a dose of 40 mg/m2 i.v. daily for 5 days every 3 -- 6 weeks. The ORR for the group was 48% and among the 62 patients treated, 20 patients (32%) achieved a CR, 1 patient a PR and 9 patients (15%) a hematologic improvement (HI). Thirteen patients (42%) achieved a CR and 4 (13%) a CRp, for an ORR of 55%. Of note, response rates were higher in patients in first salvage and a CR duration for > 12 months. Among the six patients with MDS, two patients achieved CR and two a CRp, for an ORR of 50%. ORRs were 58 and 16% in patients with CML-BP and ALL, respectively. The duration of responses ranged from 1 to 10+ months for patients with AML and ALL and the median survival was 7 months. Frequent non-hematologic adverse events included transient liver dysfunction, rash, palmoplantar erythrodyesthesia and mucositis. Among the 62 patients, 24 patients experienced transient grade 3 or 4 hepatic dysfunction. Most patients (81%) experienced febrile neutropenia and a documented infection was present in 50% of the cases. Interestingly, pharmacodynamic studies revealed the accumulation of significantly more clofarabine triphosphate in leukemic blasts in responders compared with non-responders. 8.
Oral clofarabine experience
Oral clofarabine has demonstrated anti-tumor activity in both solid and hematological tumor xenograft mouse models [5,24-26]. Clofarabine was cytotoxic at lower IC50 levels than fludarabine in vitro against numerous human cell lines including L1210 and K562 leukemic cells [6,24]. In two Phase II trials, Faderl et al. explored the safety and efficacy i.v. and oral formulations of clofarabine in 61 patients with high-risk MDS and ‡ 5% blasts or International Prognostic Scoring System (IPSS) intermediate-2 (Int-2) and high-risk, chronic myelomonocytic leukemia (CMML) and refractory cytopenias by French American British definition (Table 1) [27]. Among the 61 patients, 6 had refractory anemia (RA), refractory anemia with ring sideroblasts or refractory cytopenia with multilineage dysplasia, 17 had refractory anemia with excess blasts-1 (RAEB-1), 16 had RAEB-2, 11 had CMML and 11 had RAEB-t. Thirty-six patients were adaptively randomized (based on response) to receive clofarabine 15 or 30 mg/m2 i.v. over 1 h daily for 5 days every 4 -- 6 weeks. In the second trial, oral clofarabine was tested in 25 patients. The starting dose was 40 mg/m2 orally daily for 5 days every 4 -- 6 weeks, which was subsequently decreased to 30 mg/m2 orally daily for 5 days after 6 patients had been treated on the higher dose. Overall, 42 patients had advanced disease or poor risk 258
disease: 69% had high or Int-2 risk disease by IPSS and approximately 33% of the patients had secondary MDS. A substantial proportion of patients (64%) had failed prior therapy with either decitabine or azacitidine. A combined ORR of 47% was gained (50% with oral clofarabine, 37 -- 50% with i.v. clofarabine). A combined CR rate of 30% was obtained (29% with oral clofarabine, 25 -- 35% with i.v. clofarabine). Three patients (13%) in the oral clofarabine arm gained a HI. Common non-hematologic adverse events were nausea, vomiting, skin rash, hyperbilirubinemia and transaminase elevations. As expected in this population, myelosuppression and hospitalizations for neutropenic fever were common. Grade 3 or higher adverse events rarely occurred. Faderl et al. explored the safety and tolerability of the oral formulation of clofarabine in 32 patients with higher-risk MDS based on WHO criteria with marrow blasts ‡ 5% or IPSS intermediate or high-risk group and patients with CMML [28]. Twenty-two patients had Int-2 or high-risk by IPSS. By WHO criteria, two-thirds (68%) of the patients were diagnosed with RAEB-1 or 2. Nine patients had secondary MDS and 20 patients failed prior therapy with hypomethylating agents (HMAs). In this trial, three dose levels of oral clofarabine were explored: 20, 30 and 40 mg/m2 daily for 5 days every 4 -- 8 weeks. CR was defined as normalization of blood with neutrophils ‡ 1 109/l and a platelets ‡ 100 109/l with ‡ 5% marrow blasts and HI was defined as meeting all criteria for CR except for platelet recovery [28]. CB was defined according to the following criteria: increase of platelets by 50% and to > 30 109/l, neutrophil increase by 100% and to > 1 109/, hemoglobin increase by 2 g/dl and/or transfusion independence [28]. The ORR was 43% with eight patients achieving a CR (25%) and three patients each attained an HI (9%) and CB (9%). In those who failed HMAs, the ORR was lower at 30%; two patients achieved a CR (10%), two a HI (10%) and two a CB (10%). Additional trials are planned to define the optimal dose and schedule of i.v. and oral clofarabine in MDS.
9.
Clofarabine in combination with Ara-C
A number of biomodulating strategies have been explored to exploit the activity of Ara-C in myeloid blast cells, by increasing intracellular concentrations of Ara-C triphosphate (AraCTP), resulting in synergistic killing of myeloid leukemia cells [29-32]. These efforts have been tested and validated clinically using combinations of Ara-C with fludarabine and cladribine in adult and pediatric AML [33]. Another interesting approach involved incubation of K562 cells with clofarabine followed 3 h later by Ara-C that caused nearly a threefold increase of intracellular Ara-CTP levels relative to cells that were incubated with Ara-C alone [11,32]. Based on these compelling findings, Faderl et al. tested the clofarabine and Ara-C combination in a Phase I/II study in 32 patients with advanced acute leukemia (25 AML, 2 ALL, 4 with high-risk
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Table 1. Activity of clofarabine in higher-risk MDS responses. Study
Phase
Population
Faderl et al. [28]
II
MDS
Faderl et al. [28] Kantarjian et al. [1]
II II
Faderl et al. [35]
II
Nazha et al. [40]*
II
MDS R/R AML MDS CML-BP R/R ALL Newly diagnosed AML and MDS Post-HMA failure
Induction strategy
CLO CLO CLO CLO CLO
30/40 mg/m2/d p.o. 5-d 15 mg/m2/d i.v. 5-d 30 mg/m2/d i.v. 5-d 20/30/40 mg/m2/d p.o. 5-d 40 mg/m2/d i.v. 5-d
CLO 40 mg/m2/d i.v. 5-d followed by Ara-C 1000 mg/m2/d i.v. 5-d CLO 15 mg/mg2/d i.v. 5-d with Ara-C 20 mg s.c. b.i.d. for 7-d
N
CR no. (%)
CRi no. (%)
Overall no. (%)
24 20 16 32 31 8 11 12 60
7 (29) 7 (35) 4 (25) 8 (25) 13 (42) 2 (25) 4 (36) 1 (8) 31 (52)
2 (8) 3 (15) 2 (13) -4 (13) 2 (25) 1/2 (27) 1 (8) 5 (8)
9 (38) 10 (50) 6 (38) 8 (25) 17 (55) 4 (50) 7 (64) 2 (17) 36 (60)
24
8 (33)*
NR
12 (50)z
*CR includes patients with a CR, CRi, marrow CR. z The ORR includes four patients with an HI not shown in the table. AML: Acute myelogenous leukemia; Ara-C: Cytarabine; CLO: Clofarabine; CML-BP: Chronic myelogenous leukemia blast phase; CR: Complete remission; CRi: CR without complete recovery of counts; HI: Hematologic improvement; HMA: Hypomethylating agent; i.v.: Intravenous; MDS: Myelodysplastic syndrome; N: Number treated; NR: Not reported; p.o.: Oral; R/R: Relapsed or refractory; s.c.: Subcutaneous.
MDS defined by more than or equal to 10% blood or marrow blasts and 1 CML-BP) [34]. Clofarabine was administered at escalating doses of 15 -- 40 mg/m2 i.v. daily for 5 days (days 2 -- 6) followed 4 h later by Ara-C 1000 mg/m2 i.v. over 2 h daily for 5 days (days 1 -- 5). The dose of clofarabine in the Phase II part was 40 mg/m2 i.v. daily for 5 days. The ORR in AML was 40% (28% CR, 12% CRp). Two of the four patients (50%) with MDS achieved a CRp (CR without recovery of platelets) and none of the patients with ALL and CML responded to therapy. The median duration of remission was 3.2 months and the median overall survival (OS) was 5.5 months. Those who achieved a CR or CRp had a median survival of 7.9 months. The adverse events observed in this trial were mainly grade 2 and consisted of transient liver test abnormalities, nausea and vomiting, diarrhea, skin rashes including hand-foot syndrome and mucositis. In another Phase II trial, Faderl et al. evaluated the efficacy of clofarabine in combination with Ara-C as frontline therapy in 60 older adults (median age of 61 years) with AML or high-risk MDS (‡ 10% marrow blasts) [35]. Clofarabine was given at 40 mg/m2/day over 1 h i.v. daily for 5 days (days 2 -- 6) followed 4 h later by Ara-C at 1000 mg/m2 over 2 h i.v. daily for 5 days (days 1 -- 5). Among the 60 patients enrolled, 53 patients had AML and 8 had high-risk MDS. Overall, 36 patients (60%) responded, 31 patients (52%) achieved CR and 5 patients (8%) a CRp. Nine patients (15%) died while on study. The CR rate with this regimen is in line with the CR rates observed with other induction regimens in elderly patients with AML. Clofarabine alone or in combination with low-dose Ara-C were evaluated in 70 elderly patients (median age of 71) with previously untreated AML or high-risk MDS by WHO criteria (2 = REAB-2, 1 = CMML-1, 1 = CMML-2) [2]. The
patients were adaptively randomized to clofarabine (30 mg/m2 i.v. daily for 5 days) with or without low-dose Ara-C (20 mg/m2 subcutaneous (s.c.) daily for 14 days). Sixteen patients received single agent clofarabine and 54 patients received combination therapy. The overall CR rate was 56% and the CR rate was significantly higher with the combination (63 vs 31%; p = 0.025). Although not statistically significant, the induction mortality was lower with the combination versus clofarabine alone, 19 vs 31% (p = 0.276), respectively. The combination also demonstrated better event-free survival (7.1 vs 1.7 months; p = 0.04), but an OS benefit was not observed (11.4 vs 5.8 months; p = 0.1). More recently, Burnett et al. randomized 406 older patients (median age 74 years) with de novo AML (62%), secondary AML (24%) and high-risk MDS (15%) (10% marrow blasts) to one of two arms: clofarabine 20 mg/m2 i.v. daily for 5 days or low-dose Ara-C (LDAC)20 mg s.c. twice daily for 10 days every 6 weeks with the aim of delivering 4 courses of therapy (Table 2) [3]. The median number of courses for each group was 2. Among the 29 high-risk MDS patients in the clofarabine arm, 12 (41%) achieved a CR, whereas 6 of the 30 (20%) in the Ara-C arm achieved a CR. An overall remission rate (CR + CRi (CR without recovery of counts)) was achieved in 28% of the patients and the 2-year survival was 13%. Clofarabine significantly improved CR (22 vs 12%; hazard ratio [HR] = 0.47 [0.28 -- 0.79]; p = 0.005) and overall response (38 vs 19%; HR = 0.41 [0.26 -- 0.62]; p < 0.0001), but there was no difference in OS, explained by poorer survival in the clofarabine patients who did not gain CR (3 for clofarabine vs 4% LDAC; p = 0.02) and following relapse (0 for clofarabine vs 8% LDAC; p = 0.02) [3]. Additionally, there was no difference between the 2 arms for relapse-free survival at 2 years (20 for clofarabine vs 8% for LDAC; p = 0.2) or 2 years survival from CR (26 vs 44%; p = 0.5).
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Table 2. Clofarbine-based randomized trials in MDS. Study
Population
Induction Strategy
N
Faderl et al. [2]
Newly Dx older AML, MDS
CLO 30 mg/m2/d i.v. 5-d vs CLO + 20 mg s.c. Ara-C daily 14-d CLO 20 mg/m2/d i.v. 5-d vs Ara-C 20 mg s.c. BID 10-d
16 54
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Burnett et al. [3] Newly Dx older AML, MDS
CR no. (%) 5 (31) 34 (63)
ORR no. (%) 5 (31) 36 (67)
OS mo.
Comments
5.8 11.4
Induction mortality (31% vs 19%; p = 0.276) EFS (7.1 mo. vs 1.7 mo; p = 0.04) (p = 0.025) (p = 0.012) (p = 0.1) No OS benefit 200 44 (22) 75 (38) 11.4 MDS ORR (41% vs 20%) 206 25 (12) 40 (19) 12 Induction mortality (18% vs 12%; p = 0.2) 2-y survival nonCR (3% vs 4%; p = 0.02) (p = 0.005) (p = 0.0001) (p = 0.7) No OS benefit
AML: Acute myelogenous leukemia; Ara-C: Cytarabine; BID: Twice daily; CLO: Clofarabine; CR: Complete remission; CRi: CR without complete recovery of counts; Dx: Diagnosed; EFS: Event free survival; HMA: Hypomethylating agent; HR; Higher-risk; i.v: Intravenous; N: Number treated; ORR: Overall response rate; OS: Overall Survival; po: Oral; s.c: Subcutaneous.
Thus, suggesting this difficult-to-treat population may not require a CR for improved survival. Those who received clofarabine required significantly more support for increased myelosuppression and experienced significantly higher rates of manageable grade 3 or higher gastrointestinal and hepatic toxicity. 10.
Clofarabine post-hypomethylating failures
The prognosis for patients failing DNA HMAs is poor and therapeutic options available are limited [36-38]. Given the promising activity of clofarabine shown in prior studies in patients with AML and MDS, Lim et al. embarked on a Phase II study that evaluated the safety and efficacy of low-dose clofarabine in patients with MDS who failed prior therapy with 5-azacitidine. In this study, 10 patients with MDS of any risk group by WHO criteria, who failed to respond to 5-azacytidine after at least six cycles therapy or whose MDS progressed while on 5-azacytidine, were enrolled [39]. By WHO classification, six patients were RA, two RAEB-1, one RAEB-2 and one AML and four patients (40%) harbored poor cytogenetics. The median age of the group was 73 years (range 65 -- 78 years). Two cohorts of patients were treated with clofarabine every 4 -- 8 weeks until disease progression or intolerable toxicities. Eight patients in the first cohort were treated with intravenous clofarabine at 10 mg/m2/day (25% of standard dose) for 5 consecutive days. Since profound hematologic toxicities were observed in the patients in cohort 1, the second cohort of patients (cohort 2) received a reduced dose of intravenous clofarabine at 5 mg/m2/day for 5 days instead of the planned 15 mg/m2/day. Of note, all patients received pegfilgrastim 6 mg on day 5 of each cycle of clofarabine. A median of two cycles (range 1 -- 4) were administered. Among the nine patients evaluable for response, one patient achieved a CR, one a PR and 2 a HI for an ORR of 44%. An ORR of 67% (4/6 patients) was observed in patients with low-risk MDS by IPSS. With a median follow-up of 9 months (range 0.5 -- 23 months), the OS for the group was 50% at 12 months. 260
The median duration of response was 10 months (range 6.5 -- 15.5 months). Despite the lower-than-usual dose of clofarabine used in other studies, severe and prolonged pancytopenia occurred in all 10 patients [39]. One patient who had a history of thrombocytopenic gastrointestinal bleed died due to an intracranial bleed despite aggressive platelet support. The authors concluded that low-dose clofarabine may induce response, but with significant toxicities in patients with lowrisk MDS who fail 5-azacytidine [39]. Nazha et al. have further explored the safety and efficacy of the combination of clofarabine and LDAC in the treatment of patients with high-risk MDS who failed prior hypomethylating therapy [40]. Among the 29 patients enrolled in this study, 14 were classified as RAEB, 11 RAEB-T and 4 CMML, or by IPSS, 27 patients (93%) were classified as Int-2 or high-risk MDS. Induction therapy consisted of clofarabine 15 mg/mg2 i.v. daily for 5 days (days 1 -- 5) and Ara-C 20 mg s.c. twice daily for 7 days (days 1 -- 7). Depending on tolerability and stability of disease, a maximum of three induction cycles were allowed. Responding patients received consolidation therapy with clofarabine 15 mg/mg/m2 i.v. daily for 3 days (days 1 -- 3) and Ara-C 20 mg s.c. twice daily for 5 days (days 1 -- 5) every 4 -- 8 weeks depending on hematopoietic recovery and resolution of toxicities for a maximum of 12 cycles. Among the 24 patients evaluable for response, 8 patients (33%) achieved a CR, CRp or marrow CR and 4 (17%) HI, for an ORR of 50%. With a median follow-up of 4.9 months (range 1.9 -- 16.7 months), the median OS was 4.8 months (range 0.5 -- 13.5 months) and the 4-week mortality was 12% [41]. Common non-hematologic adverse events were nausea (31%), headache (24%), rash (28%), elevated liver enzymes (41%) and febrile neutropenia (28%). Grade 3 or higher adverse events included elevated liver enzymes (3%) and elevated bilirubin (3%). Although the response rates are promising, the role clofarabine in MDS post-hypomethylating failure is questionable.
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11.
Conclusion
Clofarabine encompasses structural features of fludarabine and cladribine that contribute to improved stability of clofarabine while retaining their beneficial properties. These interesting properties of clofarabine, as well as the need to develop new therapies for adult patients with MDS, explain the increased interest in this agent over the past decade. In addition to providing an important treatment option for pediatric patients with ALL, clofarabine also has demonstrated significant ORRs in AML and MDS. The most common clofarabinerelated adverse events observed in the treatment of AML and MDS were bone marrow suppression, nausea, vomiting, diarrhea, tachycardia, fever, fatigue, transient liver dysfunction, skin rashes, palmoplantar erythrodysesthesia and mucositis. Despite the progress in MDS, there is a major need for more effective and tolerable treatments for all adults with MDS. Further studies are needed to determine the role of clofarabine in the treatment of MDS. 12.
Expert opinion
DNA-methyltransferase inhibitors are standard of care for many patients with MDS who require treatment. Although these agents represent a significant advancement in the treatment for MDS by improving transfusion requirements and prolonging survival (azacitdine) in various subgroups of patients, response rates are modest (ORRs of 28 -- 48% with CR rates 6 -- 34%) and the duration of response is < 1 year. Furthermore, failure to respond to or relapse from treatment with HMAs carries a poor outcome and no approved therapy for these patients exists [36-38]. At this time, allogeneic stem Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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cell transplant provides the only opportunity for cure. Extensive efforts are being made to improve outcomes for patients with MDS. Clofarabine is a novel second-generation purine nucleoside analog that has demonstrated significant antitumor activity in pediatric acute leukemia. As a result, it gained approval by the FDA in 2004 for the treatment of pediatric relapsed or refractory ALL. In addition to providing a valuable treatment option for pediatric patients with ALL, clofarabine alone and in combination with Ara-C also has demonstrated substantial activity against MDS and AML in the older population. Clofarabine can be used as a bridge to transplantation in patients with MDS [41]. The role of clofarabine in MDS will be to improve outcomes by increasing the response rate and decreasing the treatment-related mortality in these patients. The pharmacologic properties of clofarabine have made of it an excellent drug to be used in combination chemotherapy regimens. Its favorable toxicity profile compared with more intensive regimens makes this agent potentially useful for elderly patients, as well. Although few studies have been done in MDS alone, promising results have been achieved with single agent clofarabine in higherrisk MDS. Nevertheless, clofarabine alone is unlikely to improve long-term survival, thus supporting the rationale to seek an effective combination regimen. Furthermore, more clinical trials are necessary to better define the subgroups of patients who would benefit from this novel drug.
Declaration of interest The authors declare no conflict of interest and have received no payment in the preparation of this manuscript.
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Affiliation Jeffrey Bryan, Hagop Kantarjian, Hillary Prescott & Elias Jabbour† MD † Author for correspondence The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd. Box 428. Houston, TX 77030, USA Tel: +1 713 792 4764; Fax: +1 713 794 4297; E-mail: [email protected]
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