Drug Evaluation
Omacetaxine mepesuccinate in chronic myeloid leukemia
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Omar Al Ustwani, Elizabeth A Griffiths, Eunice S Wang & Meir Wetzler† 1.
Introduction
Roswell Park Cancer Institute, Department of Medicine, Leukemia Section, Buffalo, NY, USA
2.
Historical overview
3.
Biologic effects
4.
Pharmacokinetics
5.
Pearls from Phase I studies
6.
Clinical studies in CML
7.
Safety
8.
Omacetaxine and the
Introduction: Homoharringtonine (HHT) and other alkaloid esters were originally isolated from the Cephalotaxus evergreen tree and have been used in traditional Chinese medicine since the 1970s to treat a variety of malignancies. Although HHT was investigated for the treatment of chronic myeloid leukemia (CML) in the 1990s with good results, the advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) at that time rapidly established a new standard of care for CML. Omacetaxine mepesuccinate is a semisynthetic derivative of HHT with known clinical activity in relapsed or refractory CML following TKI therapy. Areas covered: In this review, we summarize the biologic effects of HHT and its derivative, omacetaxine, in CML. Additionally, we analyze the concepts learned from the early trials using these drugs. Data from clinical trials resulting in drug approval are also reviewed. Expert opinion: Omacetaxine has a clear role in the CML armamentarium for patients in chronic and accelerated phase who have failed or were intolerant to two or more TKIs.
leukemia stem cell 9. 10.
Conclusion Expert opinion
Keywords: chronic myeloid leukemia, homoharringtonine, omacetaxine, tyrosine kinase inhibitor Expert Opin. Pharmacother. (2014) 15(16):2397-2405
1.
Introduction
Chronic myeloid leukemia (CML) is a hematologic condition that arises from the fusion of the Abelson tyrosine kinase (ABL1) gene (chromosome 9q34) and the breakpoint cluster region (BCR) gene (chromosome 22q11.2). This results in the formation of the Philadelphia (Ph) chromosome and leads to a constitutively activated BCR-ABL1 kinase [1]. Recognition of this aberration as the sine qua non of CML led to the clinical development of the first BCR-ABL1 tyrosine kinase inhibitor (TKI), imatinib mesylate. Imatinib became the first FDA-approved TKI for CML therapy, based on the results of the International Randomized Study of Interferon versus STI571 (IRIS) [2]. Longer clinical follow-up has highlighted the significant relapse rate of up to 20% in CML patients treated with imatinib for 6 years, which was mainly due to intolerance of the drug or primary resistance [3]. Several mechanisms of resistance to imatinib have been identified including point mutations in and around the ATP binding site of the ABL1 kinase domain [4]. Despite early and promising results of treating CML with homoharringtonine (HHT) in the 1990s [5], interest in the drug had gradually declined with the introduction of TKIs as novel targeted therapy for this disease. With the development of the newer generations TKIs, investigators realized that the challenges of compliance, refractoriness, progression and/or the evolution of new mutations were very significant. As a result, efforts were refocused on HHT and its semisynthetic derivative omacetaxine mepesuccinate (omacetaxine) (Box 1) because these drugs act through a mechanism of action distinct from the TKI. In fact, omacetaxine has been shown to induce apoptosis and decrease protein synthesis in leukemic stem cells without interacting with the BCR-ABL1 kinase domain [6]. This review focuses on the 10.1517/14656566.2014.964642 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase
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Indication
Pharmacology description Route of administration Chemical formula
Pivotal trial(s)
Omacetaxine mepesuccinate FDA approved for chronic myeloid leukemia (CML) after two Phase II trials Treatment of adult patients with chronic phase or accelerated phase CML who are resistant or intolerant to two or more tyrosine kinase inhibitors Protein synthesis inhibitor Subcutaneous 4-methyl (2R)2-hydroxy-2-(-4hydroxy-4-methylpentyl) butanedioate CML 202 and 203
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).
development of and currently available clinical data on the use of omacetaxine in CML and provides additional insight into active and potential investigations of this drug. 2.
In vitro studies of HHT in CML hematopoietic progenitors showed an inhibitory effect on cell growth in G1 and G2 phases by inducing apoptosis in a dose-dependent manner [12,13]. Semisynthetic HHT (ssHHT, omacetaxine) releases cytochrome c, decreases the mitochondrial membrane potential and activates caspase pathways in cells undergoing apoptosis [14,15]. It also downregulates expression of the antiapoptotic protein myeloid cell leukemia-1 and induces Bcell lymphoma 2 (Bcl-2) cleavage in non-Ph+ acute myeloid leukemia (AML) cell lines, HL60 and a subclone derivative (HL60/MRP) expressing of the multi-drug resistance-related protein-1 (MRP1) [14]. In addition, HHT induces differentiation of HL60 cells towards macrophage-like cells [16]. Of importance, HHT inhibits both mutated and unmutated BCR-ABL1 proteins and leukemia stem cells in murine CML and Ph+ acute lymphoblastic leukemia models [6]. It even suppresses the function of the surviving stem cells after treatment with ssHHT [17]. Doses of HHT between 10 and 1000 mg/ml are able to induce apoptosis in chronic phase (CP)-CML cells, but an effect on blastic phase (BP)-CML was only evident in the presence of IFN-a and cytarabine [12]. This may be, in part, explained by differences in the expression of glycoprotein P170 and other multi-drug resistance (MDR) proteins [18] between CP-CML and BP-CML [19]. Cell lines that overexpress the MDR1 gene have increased resistance to HHT as well as to imatinib [20]. Concomitant HHT and imatinib administration resulted in an additive effect in one study [21] and in synergistic effects in some others [22], especially when given sequentially [23].
Historical overview 4.
Esters of Caphelotaxus alkaloids extracted from different species of the Cephalotaxus harringtonia K. Koch var harringtonia evergreen tree have been used in the traditional Chinese medicine since the 1970s [7-9]. Collaboration between Chinese and American investigators resulted in the discovery that alkaloids extracted from the Cephalotaxus plant including harringtonine, HHT, isoharringtonine and deoxyharringtonine had activity against murine leukemias [7]. HHT [4-methyl (2R)-2-hydroxy-2-(-4-hydroxy-4-methylpentyl) butanedioate (ester)] was found to be the most effective alkaloid and is highly concentrated in the Celphalotaxus fortunei tree [7]. Semisynthesis of HHT was developed by direct esterification of cephalotaxine and eventually marketed and produced as subcutaneous (SC) formulation under the name omacetaxine mepesuccinate (SYRIBO, by Teva Pharmaceuticals). 3.
Biologic effects
HHT decreases protein and globin synthesis in cell cultures of HeLa cells and reticulocyte lysates at a concentration of 0.10 µM [10]. It also inhibits binding of aminocyl tRNA to the ribosome A-site on the 60S subunit, the formation of peptide bonds and the elongation of translation (Figure 1) [11]. 2398
Pharmacokinetics
Pharmacokinetic studies in humans showed that HHT has a terminal half-life of 14.4 h after a 6-h infusion [24]. CNS penetrance was also demonstrated [25]. One metabolite that has been identified is the HHT-acid which is 700 times less potent than HHT [26]. SC ssHHT has a half-life of 11 h, plasma clearance of 11.6 l/h and volume of distribution of 2 l/kg [27]. In a recent study, SC omacetaxine was given at 1.25 mg/m2 for 14 days every 28 days. Plasma and urine concentrates of omacetaxine’s two inactive metabolites, 4¢desmethylhomoharringtonine (4¢-DMHHT) and cephalotaxine were measured using a liquid chromatography--tandem mass spectrometry. SC omacetaxine was quickly absorbed into the blood with measurable plasma concentration at 0.5 h following administration. The mean half-life after the first dose was 7 h, and the volume of distribution was 126.8 l/m2. Data on the metabolite cephalotaxine were insufficient due to negligible concentration, but plasma concentrations of 4¢-DMHHT reached ~ 10% of the parent compound. Peak plasma 4¢-DMHHT concentrations were attained at ~ 3 -- 5 h after administration of omacetaxine. The elimination half-life of 4¢-DMHHT was more than twice that of omacetaxine (~ 16 h) and, in contrast to omacetaxine,
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Omacetaxine mepesuccinate
Subunit 30S 5′
3′
Subunit 50S
P
A
A site: Aminoacyl tRNA binding site P site: Peptidyl tRNA binding site
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Inhibition of translation initiation Omacetaxine
Figure 1. The main mechanism of action for omacetaxine.
the urinary excretion of 4¢-DMHHT was relatively low at 4 -- 5% [28]. 5.
Pearls from Phase I studies
HHT has been studied in a wide variety of hematologic malignancies, including CML, as summarized in a landmark paper by Grem et al. [8]. After the promising Chinese experience with HHT, a Phase I study was conducted in the US by Legha et al. to study HHT as a short daily infusion given for 10 days, with dose escalation from 0.2 to 8 mg/m2 in patients with advanced malignancies. Hypotension was identified as the dose-limiting toxicity (DLT) at doses higher than 4 mg/m2 a day [29]. Based on those results, a dose of 3 -- 4 mg/m2 short infusion daily for 5 days was recommended to be used in future Phase II studies [30]. As an alternative to overcome the toxicity, continuous infusion of HHT successfully reduced the risk of hypotension and vasodilation as long as dosing of HHT did not exceed 5 mg/m2 given for 9 days as demonstrated by Warrell et al. [31]. Myelosuppression remained the main toxicity, as it would be throughout subsequent clinical studies [31]. The first Phase I trial of SC ssHHT was done in 2006 in patients with relapse/refractory AML or myelodysplastic syndrome (MDS). Patients on the trial were treated with twice-daily SC ssHHT with dose escalation from 0.5 to 6 mg/m2 given for 9 days. Myelosuppression was seen at all doses within 31 (24 -- 45) days of therapy, and the maximum tolerated dose (MTD) was defined as 5 mg/m2 daily for 9 days. DLTs included hyperglycemia with hyperosmolar coma, anasarca with hematemesis, life-threatening pulmonary aspergillosis, skin rash and scalp pain [27]. 6.
Clinical studies in CML
HHT administered intravenously (i.v.) was used as single agent in 71 patients with CP-CML. A 28-day cycle of 2.5 mg/m2 for 14 days in induction phase, and then 7 of 28 days during maintenance resulted in complete hematologic response (CHR) in 72%, a cytogenetic response in 31% including major (complete and partial) cytogenetic responses
(MCyR) in 15%. Adverse events (AEs) included fever or infections in 26% of patients in the induction phase and in 8% during maintenance. Significant myelosuppresion was reported in 39 and 9% of induction and maintenance, respectively [5]. Combinations of HHT with low-dose cytarabine, IFN-a, both or imatinib have been investigated (Table 1) and resulted in improved cytogenetic remission [32-36]. A Phase I/II study of omacetaxine in CML showed a MTD of 1.25 mg/m2 SC twice daily in patients with accelerated phase (AP-) or BP-CML. The study was expanded to include patients with CP-CML after failing imatinib. An i.v. loading dose of 2.5 mg/m2 was given over 24 h, followed by 1.25 mg/m2 SC twice daily for 14 days every 28 days until remission, and then for 7 days every 28 days. Responses in five evaluable patients included five CHR, one complete cytogenetic response (CCyR) (in a patient with F359I mutation) and two minor cytogenetic responses (one in a patient with compound G250E and Y253H mutations). Myelosuppression occurred in all patients and prompted dose reduction in three of five patients due to prolonged neutropenia [37]. Those results provided the basis on which to use 1.25 mg/m2 twice a day SC for further clinical studies including the CML 202 and CML 203 studies, which resulted in FDA approval of omacetaxine in CML after the failure of two or more TKIs or with T315I mutation. CML 202 Patients with CML harboring the T315I mutation in the BCRABL1 kinase domain have poor survival [38] due to resistance to current TKIs (other than ponatinib) [39]. The CML 202 Phase II study was designed to focus on patients with this mutation after preclinical and preliminary clinical data suggested the efficacy of omacetaxine in this setting [6,40]. Sixty-two patients received 1.25 mg/m2 of omacetaxine SC twice a day for 14 days during induction and for 7 days during maintenance, on a 28-day schedule. The administration of hematopoietic growth factors was allowed in the event of febrile neutropenia. Erythropoiesis-stimulating agents and transfusion were allowed if required. This was a heavily pretreated patient population, of which 100% had failed imatinib and 74% had failed at least two TKIs. At the 5-year point analysis, 19% were still receiving the drug. Most of the discontinuation was due to progression or lack of response. CHR was achieved in 48/62 (77%), a cytogenetic response in 27/72 (44%) including 14 MCyR (23%) and 10 CCyR (16%). Patients received a median of seven cycles (range, 1 -- 41). The median number of cycles to achieve MCyR was 2.5 (range, 2 -- 5) with the response lasting a median of 6.6 months. At 19 months of follow-up, 68% of patients were still alive, the median progression-free survival (PFS) was 7.7 months and the median overall survival (OS) had not been reached [41]. 6.1
CML 203 Options after failing two TKIs had been limited until recently to either a third TKI or to allogeneic stem cell transplantation 6.2
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Table 1. Combination of HHT and omacetaxine with other drugs in CML. Combination
Number of patients
OMA + IM OMA + IM
14 15
OMA + IM OMA + IM + G-CSF HHT + IFN-a + ara-C HHT + ara-C HHT + ara-C HHT + IFN-a
10 11 90 100 44 37
Patients
CP-CML Resistant CP-CML and AP, BP-CML CP-CML BP-CML CP-CML Late CP-CML CP-CML CP-CML
CHR (%)
CCyR (%)
Overall cytogenetic response (%)
Ref.
66 21
17 14
50 28
Li et al. [59] Ayoubi et al. [60]
NA 61 94 72 82 89
NA 27 22 5 17* 21
50 (molecular response) 100 75 30 NA 66
Marin et al. [35] Fang et al. [61] O’Brien et al. [33] Kantarjian et al. [34] Stone et al. [36] O’Brien et al. [62]
*Only 4/23 with adequate cytogenetic assessment. AP: Accelerated phase; Ara-C: Cytarabine; BP: Blastic phase; CCyR: Complete cytogenetic response; CHR: Complete hematologic response; CML: Chronic myeloid leukemia; CP: Chronic phase; HHT: Homoharringtonine; IM: Imatinib; NA: Not available; OMA: Omacetaxine.
Table 2. Hematologic and cytogenetic responses to treatment with omacetaxine in CP-CML from the 202 and 203 trials. Response
CML 202, n (%) CML 203, n (%) n = 62 n = 67
CHR MCyR CCyR PCyR Minor cytogenetic response No cytogenetic response Not evaluable
48 (77) 14 (23) 10 (16) 4 (6) 3 (5) 23 (37) 12 (19)
31 (67) 10 (22) 2 (4) 8 (17) 7 (15) 18 (39) 11 (24)
CCyR: Complete cytogenetic response; CHR: Complete hematologic response; CML: Chronic myeloid leukemia; CP: Chronic phase; MCyR: Major cytogenetic response; PCyR: Partial cytogenetic response.
(ASCT). In CML 203, SC omacetaxine was studied in 46 patients with CP-CML resistant or intolerant to two or more TKIs. Resistance was defined as not reaching a CHR at 12 weeks of treatment, no cytogenetic response at 24 weeks, no MCyR at 52 weeks or progressive leukocytosis. Intolerance was defined as grade 3/4 nonhematologic toxicity not resolving without an intervention, any grade 4 toxicity lasting > 7 days or any grade 2 or more toxicity deemed unacceptable by the patient. SC omacetaxine was administered on the same schedule as the CML 202 trial. The primary end point was hematologic response lasting > 8 weeks, or MCyR. The study enrolled 46 patients, with a median age of 58 years (range, 20 -- 78); 85% had prior exposure to two or more TKIs, and 59% had failed three or more TKIs. At the time of analysis, 89% had discontinued the drug after receiving a median of 4.5 cycles (range, 1 -- 36), with a median exposure time to drug of 5.1 months (range, 0.2 -- 33.3). Hematologic response was achieved in 67% (31/46) of patients and lasted for a median of 7 months (range, 1.4 -- 35). MCyR was achieved 2400
in 10 of the 46 (22%) and lasted a median of 6 months (range, 1 -- 25), including two CCyR and eight partial cytogenetic responses. At a median follow-up of 19 months, the estimated PFS was 7 months (95% CI, 5.9 -- 8.9) and the OS was 30.1 months (95% CI, 20.3-not reached) [42]. Table 2 summarizes the clinical results of the CML 202 and 203 studies. Use in AP- and BP-CML AP- and BP-CML represent a challenge as they have transient response to TKIs [43], and even with ASCT their outcomes remain suboptimal especially in those without a hematologic response [44-46]. Induction chemotherapy of acute leukemia regimen could be used in myeloid BP-CML but is associated with profound toxicities [47]. The different mechanism of action of omacetaxine and its effect on the leukemia stem cell makes it an attractive option to advanced CML [17]. Patients with AP- or BP-CML (51 and 44 patients, respectively) who had resistance or intolerance to at least two TKIs or a history of T315I mutation were included as part of the CML 202 and 203 trials. Resistance to three TKIs was documented in 39% of those in AP and 48% of those in BP. The T315I mutation was documented in 39 and 48% of AP and BP, respectively. Patients received SC omacetaxine 1.25 mg/ m2 twice daily days 1 -- 14 every 28 days until hematologic response, improvement or any cytogenetic response, and then days 1 -- 7 every 28 days until disease progression. Major hematologic response was maintained or achieved in 19 of the 51 (37%) patients in AP and in 4 of the 44 (9%) in BP. MCyR was achieved in 2 of 51 (4%) patients in AP and in none of those in BP (Table 3). The median PFS was 4.8 and 2.2 months, and the median OS was 17.6 and 2.2 months in AP- and BP-CML, respectively [48]. The hematologic and cytogenetic response rates with omacetaxine were lower than those in the second-line TKIs. However, it must be highlighted that this is a heavily pretreated population with high prevalence of T315I mutation. 6.3
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Omacetaxine mepesuccinate
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Table 3. Hematologic and cytogenetic responses to treatment with omacetaxine in AP and BP-CML. Response
AP-CML, n (%) n = 51
BP-CML, n (%) n = 44
MHR CHR MCyR Minor cytogenetic response No cytogenetic response Not evaluable
19 (37) 15 (29) 2 (4) 6 (11) 25 (49) 18 (35)
4 (9) 3 (7) 0 1 (2) 15 (34) 26 (60)
AP: Accelerated phase; BP: Blastic phase; CHR: Complete hematologic response; CML: Chronic myeloid leukemia; MCyR: Major cytogenetic response; MHR: Major hematologic response.
7.
Safety
Data from the CML 202 and 203 studies [41,42,49] showed that SC omacetaxine commonly results in grade 3/4 myelosuppression. Nonhematologic AEs were predominantly mild and included diarrhea, nausea, fatigue and pyrexia. Injection-site reactions were also common with 21% of patients experiencing erythema and 10% local pain. Infections occurred in 59% and were severe (grade 3/4) in 17% of patients. Eight percent of patients treated with omacetaxine developed neutropenia. Treatment delays, most often related to myelosuppression, were common and occurred in 70 -- 76% of patients (Table 4). Death occurred in nine (CML 202) and six (CML 203) patients due to disease progression, sepsis, multi-organ failure or cerebral hemorrhage [41,42]. In the population of patients with more advanced disease (AP-CML and BP-CML), the most common grade 3/4 hematologic AEs included thrombocytopenia (51 and 21%), anemia (39 and 21%) and neutropenia (20 and 21%). Febrile neutropenia occurred in 14 and 18% of the patients in each groups. The most common nonhematologic AEs included diarrhea, nausea, fatigue and pyrexia. Death on study occurred in 4 and 19 patients with AP-CML and BP-CML, respectively [48]. A recent pooled safety analysis in patients treated with omacetaxine confirmed an acceptable safety and tolerability profile in patients with CML [49-51]. Another strong position of omacetaxine for using in T315Imutated CML is the vascular thrombotic events due to ponatinib, the usual candidate drug for T315I. Recently, the FDA (safety announcement 2013:10-1-2013) has suspended the development of ponatinib in response to the vascular toxicity concerns from the 24-month review of the PACE Phase II trial that enrolled patients who were resistant or intolerant to dasatinib or nilotinib or harbored a T315I mutation. The safety data of the PACE trial disclosed non-serious and serious arterial and venous AEs combined occurred in ~ 20% of ponatinib-treated patients (cardiovascular events 6.2%, cerebrovascular events 4%, peripheral vascular events 3.6%, venous occlusion 2.9%). Furthermore, ABL kinases are critical for the vascular development and endothelial cell
survival. The loss of endothelial ABL kinases in the genetic model results in cardiac enlargement and scarring, lung fibrosis, thrombosis and cumulative vascular stresses. Therefore, the already observed vascular thrombotic events of ponatinib may be considered as a ‘class effect’ of TKIs [52]. 8.
Omacetaxine and the leukemia stem cell
The bone marrow microenvironment and leukemic stem cells play an important role in CML progression. This creates an opportunity to study the effect of omacetaxine as a curative therapy because TKIs are ineffective in this setting. A murine model of BCR-ABL1-induced leukemia was used to investigate the effect of omacetaxine against CML stem cells. Survival of the Lin- Sca+cKit+ (LSK population, used to identify leukemic stem cells) was demonstrated in a dosedependent manner after 6 days in culture with omacetaxine. The same inhibited growth of this fraction was noted in vivo using flow cytometry on leukemic bone marrow harvested from mice treated with omacetaxine [6]. Another study demonstrated that omacetaxine was able to induce apoptosis in CD34+ primitive stem cell subpopulation and eventually preventing colony formation [17]. Additional insight was demonstrated via the in vitro data on the KCL22, a human BP-CML cell line that is insensitive to imatinib. Omacetaxine, when pulsed 24 h prior to incubating KCL22 cells with imatinib, was more lethal than the reverse order of the combination. This has been explained by blocking the accumulation of Bcl-2 interacting mediator of cell death, a critical key for imatinib to be able to induce apoptosis [17]. These preclinical data support the hypothesis that omacetaxine together with TKIs might target the leukemic stem cell and thereby eradicate minimal residual CML disease. In another in vitro study, omacetaxine’s downregulation of the b subunit of the IL-3-receptor represents an attractive option to target IL-3 and other cytokine-dependent pathways that are crucial for the leukemia stem cell survival. This could be another strategy to further evaluate its potential to overcome cytokine-dependent resistance against TKIs [53,54]. 9.
Conclusion
Omacetaxine has been approved by the FDA based on favorable benefit and tolerability profile in adult patients with CP or AP CML that are resistant to or intolerant of TKIs. 10.
Expert opinion
Omacetaxine provides an alternative for CML patients who have demonstrated resistance or intolerance to TKIs. This agent has a distinct mechanism of action and may be able to eradicate leukemic stem cells that are believed to play a pivotal role in disease progression. Furthermore, there is evidence for activity of this agent, on mutations that are resistant to ponatinib. Recent preclinical data have
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Table 4. The most common AEs occurring in patients with CP-, AP- and BP-CML patients treated with omacetaxine per CML 202 and 203. CP-CML 202 (n = 62)
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All grades Hematologic AEs, n (%) Thrombocytopenia 49 (79) Anemia 41 (66) Neutropenia 31 (50) Febrile neutropenia 5 (8) Nonhematologic AEs, n (%) Diarrhea 25 (40) Nausea 21 (34) Pyrexia 18 (29) Fatigue 18 (29) Injection-site erythema 31 (21)
CP-CML 203 (n = 67)
AP-CML (n = 51)
BP-CML (n = 44)
Grade $ 3
All grades
Grade $ 3
All grades
Grade $ 3
All grades
Grade $ 3
47 (76) 24 (39) 27 (44) N/A
31 (67) 25 (54) 23 (50) 7 (15)
25 (54) 15 (33) 22 (48) 7 (15)
31 27 11 10
26 (51) 20 (39) 10 (20) 7 (14)
16 13 11 19
13 (30) 9 (21) 9 (21) 8 (18)
1 1 1 3 0
20 (44) 14 (30) 9 (20) 11 (24) 8 (17)
0 0 0 2 (4) 0
18 (35) 14 (28) 16 (31) 16 (31) N/A
4 (8) 1 (2) 1 (2) 5 (10) N/A
18 (41) 12 (27) 14 (32) 10 (23) N/A
(2) (2) (2) (5)
(61) (53) (25) (23)
(36) (30) (25) (23)
2 (5) 1 (2) 1 (2) 2 (5) N/A
AEs: Adverse events; AP: Accelerated phase; BP: Blastic phase; CML: Chronic myeloid leukemia; CP: Chronic phase; N/A: Information not available.
demonstrated the activity of omacetaxine in a Ba/F3 ponatinib-resistant cell line harboring compound mutations (Y253H, E255K and T315I). After incubation for 48 -72 h, the investigators observed reduced cell growth, increased apoptosis and decrease phosphorylation of BCRABL1 and other down-stream pathways [55]. Given the increasing recognition of compound mutations as a resistance mechanism in CML, it will be of considerable interest to follow omacetaxine in the evolving paradigm of CML treatment. This is especially true as imatinib will be coming off patent in 2016 and with the re-positioning of ponatinib exclusively to the second- or third-line setting. Active research on the clinical application of omacetaxine is ongoing in different hematologic malignancies. This could be emerging as an important therapy for entities where imatinib is generally used but specific mutations deem it ineffective. For example, The Kit receptor mutations are critical in the pathogenesis of systemic mastocytosis. However, the loop mutation D816V or D814Y is resistant to imatinib. HHT showed promising results in the murine model that could provide the theoretical base to clinically investigate its role in systemic mastocytosis patients harboring D816V or D814Y mutations [56]. Also, efforts to investigate omacetaxine in combination with low-dose cytarabine or hypomethylating agents in the elderly AML, or in MDS patients who failed standard therapy, are all of special interest and currently ongoing. Another area of investigation is the combination of omacetaxine with the currently available TKIs in CML. One initial drawback to the use of omacetaxine was the restriction imposed by the FDA requiring that this agent be given exclusively in the healthcare setting, making the twicedaily injection schedule a significant challenge. This restriction has recently been lifted, and the FDA has now approved the use of omacetaxine for home injection [49]. This point requires special attention as the drug comes in single dose 3.5 mg vials, and the average drug given in CML was 2402
2.4 mg. Emphasis to avoid overdosing should take place when reviewing instructions with patients. Another general issue to consider when choosing the optimal drug for CML is the concern of overtreatment or undertreatment during the long-term clinical course of CML. An example of overtreatment is the aggressive therapeutic intervention during the CML management when a drug exhibits suboptimal response by proceeding onto ASCT when other drugs could be used effectively. On the other hand, undertreatment represents the phenomenon of insufficient intervention during the management when early signs of drug failure are noticed, resulting in disease progression and detrimental outcomes [57]. This is more relevant in the front-line setting and choice of TKIs per the European Leukemia Network recommendations. However, the concept could be projected and applied at the critical point upon the consideration of initiating omacetaxine; then again when observing lack or loss of response on omacetaxine. Pharmacoeconomy and cost are emerging as important factors in the choice of drugs in CML management. Omacetaxine is no exception of the expensive arsenal of CML drugs, with 28,000 $ as the cost of induction and 14,000 $ per maintenance course. The high cost of CML drugs, in general, is finally gaining more attention by the experts in the field to address its reasons and to propose solutions to reduce it to make these drugs more available to the affected patients [58].
Declaration of interest The paper was supported partially by grants from the National Cancer Institute Grant CA16056 (OA Ustwani, EA Griffiths, ES Wang, M Wetzler), the Cancer Clinical Investigator Team Leadership Award (CCITLA) awarded by the National Cancer Institute through a supplement to P30CA016056 (ES Wang), the Szefel Foundation, Roswell Park Cancer Institute, the Leonard S. LuVullo Endowment for Leukemia Research, the Nancy C. Cully Endowment for Leukemia Research, the
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Babcock Family Endowment and the Heidi Leukemia Research Fund, Buffalo, NY. M Wetzler was an investigator on the 202 and 203 studies, is a current investigator on other omacetaxine trials and served as a consultant for Teva. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Jabbour E, Garcia-Manero G, Cortes J, et al. Twice-daily fludarabine and cytarabine combination with or without gentuzumab ozogamicin is effective in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and blastphase chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk 2012;12(4):244-51
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Cortes JE, Nicolini FE, Wetzler M, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk 2013;13(5):584-91 One of the two Phase II trials that led to the FDA approval of omacetaxine in CML.
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Affiliation Omar Al Ustwani MD, Elizabeth A Griffiths MD, Eunice S Wang MD & Meir Wetzler† MD † Author for correspondence Roswell Park Cancer Institute, Department of Medicine, Leukemia Section, Elm and Carlton Street, Buffalo, NY 14263, USA Tel: +001 716 845 8447; Fax: +001 716 845 2343; E-mail: [email protected]
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Omacetaxine mepesuccinate in chronic myeloid leukemia
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Omar Al Ustwani, Elizabeth A Griffiths, Eunice S Wang & Meir Wetzler† 1.
Introduction
Roswell Park Cancer Institute, Department of Medicine, Leukemia Section, Buffalo, NY, USA
2.
Historical overview
3.
Biologic effects
4.
Pharmacokinetics
5.
Pearls from Phase I studies
6.
Clinical studies in CML
7.
Safety
8.
Omacetaxine and the
Introduction: Homoharringtonine (HHT) and other alkaloid esters were originally isolated from the Cephalotaxus evergreen tree and have been used in traditional Chinese medicine since the 1970s to treat a variety of malignancies. Although HHT was investigated for the treatment of chronic myeloid leukemia (CML) in the 1990s with good results, the advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) at that time rapidly established a new standard of care for CML. Omacetaxine mepesuccinate is a semisynthetic derivative of HHT with known clinical activity in relapsed or refractory CML following TKI therapy. Areas covered: In this review, we summarize the biologic effects of HHT and its derivative, omacetaxine, in CML. Additionally, we analyze the concepts learned from the early trials using these drugs. Data from clinical trials resulting in drug approval are also reviewed. Expert opinion: Omacetaxine has a clear role in the CML armamentarium for patients in chronic and accelerated phase who have failed or were intolerant to two or more TKIs.
leukemia stem cell 9. 10.
Conclusion Expert opinion
Keywords: chronic myeloid leukemia, homoharringtonine, omacetaxine, tyrosine kinase inhibitor Expert Opin. Pharmacother. (2014) 15(16):2397-2405
1.
Introduction
Chronic myeloid leukemia (CML) is a hematologic condition that arises from the fusion of the Abelson tyrosine kinase (ABL1) gene (chromosome 9q34) and the breakpoint cluster region (BCR) gene (chromosome 22q11.2). This results in the formation of the Philadelphia (Ph) chromosome and leads to a constitutively activated BCR-ABL1 kinase [1]. Recognition of this aberration as the sine qua non of CML led to the clinical development of the first BCR-ABL1 tyrosine kinase inhibitor (TKI), imatinib mesylate. Imatinib became the first FDA-approved TKI for CML therapy, based on the results of the International Randomized Study of Interferon versus STI571 (IRIS) [2]. Longer clinical follow-up has highlighted the significant relapse rate of up to 20% in CML patients treated with imatinib for 6 years, which was mainly due to intolerance of the drug or primary resistance [3]. Several mechanisms of resistance to imatinib have been identified including point mutations in and around the ATP binding site of the ABL1 kinase domain [4]. Despite early and promising results of treating CML with homoharringtonine (HHT) in the 1990s [5], interest in the drug had gradually declined with the introduction of TKIs as novel targeted therapy for this disease. With the development of the newer generations TKIs, investigators realized that the challenges of compliance, refractoriness, progression and/or the evolution of new mutations were very significant. As a result, efforts were refocused on HHT and its semisynthetic derivative omacetaxine mepesuccinate (omacetaxine) (Box 1) because these drugs act through a mechanism of action distinct from the TKI. In fact, omacetaxine has been shown to induce apoptosis and decrease protein synthesis in leukemic stem cells without interacting with the BCR-ABL1 kinase domain [6]. This review focuses on the 10.1517/14656566.2014.964642 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase
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Indication
Pharmacology description Route of administration Chemical formula
Pivotal trial(s)
Omacetaxine mepesuccinate FDA approved for chronic myeloid leukemia (CML) after two Phase II trials Treatment of adult patients with chronic phase or accelerated phase CML who are resistant or intolerant to two or more tyrosine kinase inhibitors Protein synthesis inhibitor Subcutaneous 4-methyl (2R)2-hydroxy-2-(-4hydroxy-4-methylpentyl) butanedioate CML 202 and 203
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).
development of and currently available clinical data on the use of omacetaxine in CML and provides additional insight into active and potential investigations of this drug. 2.
In vitro studies of HHT in CML hematopoietic progenitors showed an inhibitory effect on cell growth in G1 and G2 phases by inducing apoptosis in a dose-dependent manner [12,13]. Semisynthetic HHT (ssHHT, omacetaxine) releases cytochrome c, decreases the mitochondrial membrane potential and activates caspase pathways in cells undergoing apoptosis [14,15]. It also downregulates expression of the antiapoptotic protein myeloid cell leukemia-1 and induces Bcell lymphoma 2 (Bcl-2) cleavage in non-Ph+ acute myeloid leukemia (AML) cell lines, HL60 and a subclone derivative (HL60/MRP) expressing of the multi-drug resistance-related protein-1 (MRP1) [14]. In addition, HHT induces differentiation of HL60 cells towards macrophage-like cells [16]. Of importance, HHT inhibits both mutated and unmutated BCR-ABL1 proteins and leukemia stem cells in murine CML and Ph+ acute lymphoblastic leukemia models [6]. It even suppresses the function of the surviving stem cells after treatment with ssHHT [17]. Doses of HHT between 10 and 1000 mg/ml are able to induce apoptosis in chronic phase (CP)-CML cells, but an effect on blastic phase (BP)-CML was only evident in the presence of IFN-a and cytarabine [12]. This may be, in part, explained by differences in the expression of glycoprotein P170 and other multi-drug resistance (MDR) proteins [18] between CP-CML and BP-CML [19]. Cell lines that overexpress the MDR1 gene have increased resistance to HHT as well as to imatinib [20]. Concomitant HHT and imatinib administration resulted in an additive effect in one study [21] and in synergistic effects in some others [22], especially when given sequentially [23].
Historical overview 4.
Esters of Caphelotaxus alkaloids extracted from different species of the Cephalotaxus harringtonia K. Koch var harringtonia evergreen tree have been used in the traditional Chinese medicine since the 1970s [7-9]. Collaboration between Chinese and American investigators resulted in the discovery that alkaloids extracted from the Cephalotaxus plant including harringtonine, HHT, isoharringtonine and deoxyharringtonine had activity against murine leukemias [7]. HHT [4-methyl (2R)-2-hydroxy-2-(-4-hydroxy-4-methylpentyl) butanedioate (ester)] was found to be the most effective alkaloid and is highly concentrated in the Celphalotaxus fortunei tree [7]. Semisynthesis of HHT was developed by direct esterification of cephalotaxine and eventually marketed and produced as subcutaneous (SC) formulation under the name omacetaxine mepesuccinate (SYRIBO, by Teva Pharmaceuticals). 3.
Biologic effects
HHT decreases protein and globin synthesis in cell cultures of HeLa cells and reticulocyte lysates at a concentration of 0.10 µM [10]. It also inhibits binding of aminocyl tRNA to the ribosome A-site on the 60S subunit, the formation of peptide bonds and the elongation of translation (Figure 1) [11]. 2398
Pharmacokinetics
Pharmacokinetic studies in humans showed that HHT has a terminal half-life of 14.4 h after a 6-h infusion [24]. CNS penetrance was also demonstrated [25]. One metabolite that has been identified is the HHT-acid which is 700 times less potent than HHT [26]. SC ssHHT has a half-life of 11 h, plasma clearance of 11.6 l/h and volume of distribution of 2 l/kg [27]. In a recent study, SC omacetaxine was given at 1.25 mg/m2 for 14 days every 28 days. Plasma and urine concentrates of omacetaxine’s two inactive metabolites, 4¢desmethylhomoharringtonine (4¢-DMHHT) and cephalotaxine were measured using a liquid chromatography--tandem mass spectrometry. SC omacetaxine was quickly absorbed into the blood with measurable plasma concentration at 0.5 h following administration. The mean half-life after the first dose was 7 h, and the volume of distribution was 126.8 l/m2. Data on the metabolite cephalotaxine were insufficient due to negligible concentration, but plasma concentrations of 4¢-DMHHT reached ~ 10% of the parent compound. Peak plasma 4¢-DMHHT concentrations were attained at ~ 3 -- 5 h after administration of omacetaxine. The elimination half-life of 4¢-DMHHT was more than twice that of omacetaxine (~ 16 h) and, in contrast to omacetaxine,
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Omacetaxine mepesuccinate
Subunit 30S 5′
3′
Subunit 50S
P
A
A site: Aminoacyl tRNA binding site P site: Peptidyl tRNA binding site
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Inhibition of translation initiation Omacetaxine
Figure 1. The main mechanism of action for omacetaxine.
the urinary excretion of 4¢-DMHHT was relatively low at 4 -- 5% [28]. 5.
Pearls from Phase I studies
HHT has been studied in a wide variety of hematologic malignancies, including CML, as summarized in a landmark paper by Grem et al. [8]. After the promising Chinese experience with HHT, a Phase I study was conducted in the US by Legha et al. to study HHT as a short daily infusion given for 10 days, with dose escalation from 0.2 to 8 mg/m2 in patients with advanced malignancies. Hypotension was identified as the dose-limiting toxicity (DLT) at doses higher than 4 mg/m2 a day [29]. Based on those results, a dose of 3 -- 4 mg/m2 short infusion daily for 5 days was recommended to be used in future Phase II studies [30]. As an alternative to overcome the toxicity, continuous infusion of HHT successfully reduced the risk of hypotension and vasodilation as long as dosing of HHT did not exceed 5 mg/m2 given for 9 days as demonstrated by Warrell et al. [31]. Myelosuppression remained the main toxicity, as it would be throughout subsequent clinical studies [31]. The first Phase I trial of SC ssHHT was done in 2006 in patients with relapse/refractory AML or myelodysplastic syndrome (MDS). Patients on the trial were treated with twice-daily SC ssHHT with dose escalation from 0.5 to 6 mg/m2 given for 9 days. Myelosuppression was seen at all doses within 31 (24 -- 45) days of therapy, and the maximum tolerated dose (MTD) was defined as 5 mg/m2 daily for 9 days. DLTs included hyperglycemia with hyperosmolar coma, anasarca with hematemesis, life-threatening pulmonary aspergillosis, skin rash and scalp pain [27]. 6.
Clinical studies in CML
HHT administered intravenously (i.v.) was used as single agent in 71 patients with CP-CML. A 28-day cycle of 2.5 mg/m2 for 14 days in induction phase, and then 7 of 28 days during maintenance resulted in complete hematologic response (CHR) in 72%, a cytogenetic response in 31% including major (complete and partial) cytogenetic responses
(MCyR) in 15%. Adverse events (AEs) included fever or infections in 26% of patients in the induction phase and in 8% during maintenance. Significant myelosuppresion was reported in 39 and 9% of induction and maintenance, respectively [5]. Combinations of HHT with low-dose cytarabine, IFN-a, both or imatinib have been investigated (Table 1) and resulted in improved cytogenetic remission [32-36]. A Phase I/II study of omacetaxine in CML showed a MTD of 1.25 mg/m2 SC twice daily in patients with accelerated phase (AP-) or BP-CML. The study was expanded to include patients with CP-CML after failing imatinib. An i.v. loading dose of 2.5 mg/m2 was given over 24 h, followed by 1.25 mg/m2 SC twice daily for 14 days every 28 days until remission, and then for 7 days every 28 days. Responses in five evaluable patients included five CHR, one complete cytogenetic response (CCyR) (in a patient with F359I mutation) and two minor cytogenetic responses (one in a patient with compound G250E and Y253H mutations). Myelosuppression occurred in all patients and prompted dose reduction in three of five patients due to prolonged neutropenia [37]. Those results provided the basis on which to use 1.25 mg/m2 twice a day SC for further clinical studies including the CML 202 and CML 203 studies, which resulted in FDA approval of omacetaxine in CML after the failure of two or more TKIs or with T315I mutation. CML 202 Patients with CML harboring the T315I mutation in the BCRABL1 kinase domain have poor survival [38] due to resistance to current TKIs (other than ponatinib) [39]. The CML 202 Phase II study was designed to focus on patients with this mutation after preclinical and preliminary clinical data suggested the efficacy of omacetaxine in this setting [6,40]. Sixty-two patients received 1.25 mg/m2 of omacetaxine SC twice a day for 14 days during induction and for 7 days during maintenance, on a 28-day schedule. The administration of hematopoietic growth factors was allowed in the event of febrile neutropenia. Erythropoiesis-stimulating agents and transfusion were allowed if required. This was a heavily pretreated patient population, of which 100% had failed imatinib and 74% had failed at least two TKIs. At the 5-year point analysis, 19% were still receiving the drug. Most of the discontinuation was due to progression or lack of response. CHR was achieved in 48/62 (77%), a cytogenetic response in 27/72 (44%) including 14 MCyR (23%) and 10 CCyR (16%). Patients received a median of seven cycles (range, 1 -- 41). The median number of cycles to achieve MCyR was 2.5 (range, 2 -- 5) with the response lasting a median of 6.6 months. At 19 months of follow-up, 68% of patients were still alive, the median progression-free survival (PFS) was 7.7 months and the median overall survival (OS) had not been reached [41]. 6.1
CML 203 Options after failing two TKIs had been limited until recently to either a third TKI or to allogeneic stem cell transplantation 6.2
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Table 1. Combination of HHT and omacetaxine with other drugs in CML. Combination
Number of patients
OMA + IM OMA + IM
14 15
OMA + IM OMA + IM + G-CSF HHT + IFN-a + ara-C HHT + ara-C HHT + ara-C HHT + IFN-a
10 11 90 100 44 37
Patients
CP-CML Resistant CP-CML and AP, BP-CML CP-CML BP-CML CP-CML Late CP-CML CP-CML CP-CML
CHR (%)
CCyR (%)
Overall cytogenetic response (%)
Ref.
66 21
17 14
50 28
Li et al. [59] Ayoubi et al. [60]
NA 61 94 72 82 89
NA 27 22 5 17* 21
50 (molecular response) 100 75 30 NA 66
Marin et al. [35] Fang et al. [61] O’Brien et al. [33] Kantarjian et al. [34] Stone et al. [36] O’Brien et al. [62]
*Only 4/23 with adequate cytogenetic assessment. AP: Accelerated phase; Ara-C: Cytarabine; BP: Blastic phase; CCyR: Complete cytogenetic response; CHR: Complete hematologic response; CML: Chronic myeloid leukemia; CP: Chronic phase; HHT: Homoharringtonine; IM: Imatinib; NA: Not available; OMA: Omacetaxine.
Table 2. Hematologic and cytogenetic responses to treatment with omacetaxine in CP-CML from the 202 and 203 trials. Response
CML 202, n (%) CML 203, n (%) n = 62 n = 67
CHR MCyR CCyR PCyR Minor cytogenetic response No cytogenetic response Not evaluable
48 (77) 14 (23) 10 (16) 4 (6) 3 (5) 23 (37) 12 (19)
31 (67) 10 (22) 2 (4) 8 (17) 7 (15) 18 (39) 11 (24)
CCyR: Complete cytogenetic response; CHR: Complete hematologic response; CML: Chronic myeloid leukemia; CP: Chronic phase; MCyR: Major cytogenetic response; PCyR: Partial cytogenetic response.
(ASCT). In CML 203, SC omacetaxine was studied in 46 patients with CP-CML resistant or intolerant to two or more TKIs. Resistance was defined as not reaching a CHR at 12 weeks of treatment, no cytogenetic response at 24 weeks, no MCyR at 52 weeks or progressive leukocytosis. Intolerance was defined as grade 3/4 nonhematologic toxicity not resolving without an intervention, any grade 4 toxicity lasting > 7 days or any grade 2 or more toxicity deemed unacceptable by the patient. SC omacetaxine was administered on the same schedule as the CML 202 trial. The primary end point was hematologic response lasting > 8 weeks, or MCyR. The study enrolled 46 patients, with a median age of 58 years (range, 20 -- 78); 85% had prior exposure to two or more TKIs, and 59% had failed three or more TKIs. At the time of analysis, 89% had discontinued the drug after receiving a median of 4.5 cycles (range, 1 -- 36), with a median exposure time to drug of 5.1 months (range, 0.2 -- 33.3). Hematologic response was achieved in 67% (31/46) of patients and lasted for a median of 7 months (range, 1.4 -- 35). MCyR was achieved 2400
in 10 of the 46 (22%) and lasted a median of 6 months (range, 1 -- 25), including two CCyR and eight partial cytogenetic responses. At a median follow-up of 19 months, the estimated PFS was 7 months (95% CI, 5.9 -- 8.9) and the OS was 30.1 months (95% CI, 20.3-not reached) [42]. Table 2 summarizes the clinical results of the CML 202 and 203 studies. Use in AP- and BP-CML AP- and BP-CML represent a challenge as they have transient response to TKIs [43], and even with ASCT their outcomes remain suboptimal especially in those without a hematologic response [44-46]. Induction chemotherapy of acute leukemia regimen could be used in myeloid BP-CML but is associated with profound toxicities [47]. The different mechanism of action of omacetaxine and its effect on the leukemia stem cell makes it an attractive option to advanced CML [17]. Patients with AP- or BP-CML (51 and 44 patients, respectively) who had resistance or intolerance to at least two TKIs or a history of T315I mutation were included as part of the CML 202 and 203 trials. Resistance to three TKIs was documented in 39% of those in AP and 48% of those in BP. The T315I mutation was documented in 39 and 48% of AP and BP, respectively. Patients received SC omacetaxine 1.25 mg/ m2 twice daily days 1 -- 14 every 28 days until hematologic response, improvement or any cytogenetic response, and then days 1 -- 7 every 28 days until disease progression. Major hematologic response was maintained or achieved in 19 of the 51 (37%) patients in AP and in 4 of the 44 (9%) in BP. MCyR was achieved in 2 of 51 (4%) patients in AP and in none of those in BP (Table 3). The median PFS was 4.8 and 2.2 months, and the median OS was 17.6 and 2.2 months in AP- and BP-CML, respectively [48]. The hematologic and cytogenetic response rates with omacetaxine were lower than those in the second-line TKIs. However, it must be highlighted that this is a heavily pretreated population with high prevalence of T315I mutation. 6.3
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Table 3. Hematologic and cytogenetic responses to treatment with omacetaxine in AP and BP-CML. Response
AP-CML, n (%) n = 51
BP-CML, n (%) n = 44
MHR CHR MCyR Minor cytogenetic response No cytogenetic response Not evaluable
19 (37) 15 (29) 2 (4) 6 (11) 25 (49) 18 (35)
4 (9) 3 (7) 0 1 (2) 15 (34) 26 (60)
AP: Accelerated phase; BP: Blastic phase; CHR: Complete hematologic response; CML: Chronic myeloid leukemia; MCyR: Major cytogenetic response; MHR: Major hematologic response.
7.
Safety
Data from the CML 202 and 203 studies [41,42,49] showed that SC omacetaxine commonly results in grade 3/4 myelosuppression. Nonhematologic AEs were predominantly mild and included diarrhea, nausea, fatigue and pyrexia. Injection-site reactions were also common with 21% of patients experiencing erythema and 10% local pain. Infections occurred in 59% and were severe (grade 3/4) in 17% of patients. Eight percent of patients treated with omacetaxine developed neutropenia. Treatment delays, most often related to myelosuppression, were common and occurred in 70 -- 76% of patients (Table 4). Death occurred in nine (CML 202) and six (CML 203) patients due to disease progression, sepsis, multi-organ failure or cerebral hemorrhage [41,42]. In the population of patients with more advanced disease (AP-CML and BP-CML), the most common grade 3/4 hematologic AEs included thrombocytopenia (51 and 21%), anemia (39 and 21%) and neutropenia (20 and 21%). Febrile neutropenia occurred in 14 and 18% of the patients in each groups. The most common nonhematologic AEs included diarrhea, nausea, fatigue and pyrexia. Death on study occurred in 4 and 19 patients with AP-CML and BP-CML, respectively [48]. A recent pooled safety analysis in patients treated with omacetaxine confirmed an acceptable safety and tolerability profile in patients with CML [49-51]. Another strong position of omacetaxine for using in T315Imutated CML is the vascular thrombotic events due to ponatinib, the usual candidate drug for T315I. Recently, the FDA (safety announcement 2013:10-1-2013) has suspended the development of ponatinib in response to the vascular toxicity concerns from the 24-month review of the PACE Phase II trial that enrolled patients who were resistant or intolerant to dasatinib or nilotinib or harbored a T315I mutation. The safety data of the PACE trial disclosed non-serious and serious arterial and venous AEs combined occurred in ~ 20% of ponatinib-treated patients (cardiovascular events 6.2%, cerebrovascular events 4%, peripheral vascular events 3.6%, venous occlusion 2.9%). Furthermore, ABL kinases are critical for the vascular development and endothelial cell
survival. The loss of endothelial ABL kinases in the genetic model results in cardiac enlargement and scarring, lung fibrosis, thrombosis and cumulative vascular stresses. Therefore, the already observed vascular thrombotic events of ponatinib may be considered as a ‘class effect’ of TKIs [52]. 8.
Omacetaxine and the leukemia stem cell
The bone marrow microenvironment and leukemic stem cells play an important role in CML progression. This creates an opportunity to study the effect of omacetaxine as a curative therapy because TKIs are ineffective in this setting. A murine model of BCR-ABL1-induced leukemia was used to investigate the effect of omacetaxine against CML stem cells. Survival of the Lin- Sca+cKit+ (LSK population, used to identify leukemic stem cells) was demonstrated in a dosedependent manner after 6 days in culture with omacetaxine. The same inhibited growth of this fraction was noted in vivo using flow cytometry on leukemic bone marrow harvested from mice treated with omacetaxine [6]. Another study demonstrated that omacetaxine was able to induce apoptosis in CD34+ primitive stem cell subpopulation and eventually preventing colony formation [17]. Additional insight was demonstrated via the in vitro data on the KCL22, a human BP-CML cell line that is insensitive to imatinib. Omacetaxine, when pulsed 24 h prior to incubating KCL22 cells with imatinib, was more lethal than the reverse order of the combination. This has been explained by blocking the accumulation of Bcl-2 interacting mediator of cell death, a critical key for imatinib to be able to induce apoptosis [17]. These preclinical data support the hypothesis that omacetaxine together with TKIs might target the leukemic stem cell and thereby eradicate minimal residual CML disease. In another in vitro study, omacetaxine’s downregulation of the b subunit of the IL-3-receptor represents an attractive option to target IL-3 and other cytokine-dependent pathways that are crucial for the leukemia stem cell survival. This could be another strategy to further evaluate its potential to overcome cytokine-dependent resistance against TKIs [53,54]. 9.
Conclusion
Omacetaxine has been approved by the FDA based on favorable benefit and tolerability profile in adult patients with CP or AP CML that are resistant to or intolerant of TKIs. 10.
Expert opinion
Omacetaxine provides an alternative for CML patients who have demonstrated resistance or intolerance to TKIs. This agent has a distinct mechanism of action and may be able to eradicate leukemic stem cells that are believed to play a pivotal role in disease progression. Furthermore, there is evidence for activity of this agent, on mutations that are resistant to ponatinib. Recent preclinical data have
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Table 4. The most common AEs occurring in patients with CP-, AP- and BP-CML patients treated with omacetaxine per CML 202 and 203. CP-CML 202 (n = 62)
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All grades Hematologic AEs, n (%) Thrombocytopenia 49 (79) Anemia 41 (66) Neutropenia 31 (50) Febrile neutropenia 5 (8) Nonhematologic AEs, n (%) Diarrhea 25 (40) Nausea 21 (34) Pyrexia 18 (29) Fatigue 18 (29) Injection-site erythema 31 (21)
CP-CML 203 (n = 67)
AP-CML (n = 51)
BP-CML (n = 44)
Grade $ 3
All grades
Grade $ 3
All grades
Grade $ 3
All grades
Grade $ 3
47 (76) 24 (39) 27 (44) N/A
31 (67) 25 (54) 23 (50) 7 (15)
25 (54) 15 (33) 22 (48) 7 (15)
31 27 11 10
26 (51) 20 (39) 10 (20) 7 (14)
16 13 11 19
13 (30) 9 (21) 9 (21) 8 (18)
1 1 1 3 0
20 (44) 14 (30) 9 (20) 11 (24) 8 (17)
0 0 0 2 (4) 0
18 (35) 14 (28) 16 (31) 16 (31) N/A
4 (8) 1 (2) 1 (2) 5 (10) N/A
18 (41) 12 (27) 14 (32) 10 (23) N/A
(2) (2) (2) (5)
(61) (53) (25) (23)
(36) (30) (25) (23)
2 (5) 1 (2) 1 (2) 2 (5) N/A
AEs: Adverse events; AP: Accelerated phase; BP: Blastic phase; CML: Chronic myeloid leukemia; CP: Chronic phase; N/A: Information not available.
demonstrated the activity of omacetaxine in a Ba/F3 ponatinib-resistant cell line harboring compound mutations (Y253H, E255K and T315I). After incubation for 48 -72 h, the investigators observed reduced cell growth, increased apoptosis and decrease phosphorylation of BCRABL1 and other down-stream pathways [55]. Given the increasing recognition of compound mutations as a resistance mechanism in CML, it will be of considerable interest to follow omacetaxine in the evolving paradigm of CML treatment. This is especially true as imatinib will be coming off patent in 2016 and with the re-positioning of ponatinib exclusively to the second- or third-line setting. Active research on the clinical application of omacetaxine is ongoing in different hematologic malignancies. This could be emerging as an important therapy for entities where imatinib is generally used but specific mutations deem it ineffective. For example, The Kit receptor mutations are critical in the pathogenesis of systemic mastocytosis. However, the loop mutation D816V or D814Y is resistant to imatinib. HHT showed promising results in the murine model that could provide the theoretical base to clinically investigate its role in systemic mastocytosis patients harboring D816V or D814Y mutations [56]. Also, efforts to investigate omacetaxine in combination with low-dose cytarabine or hypomethylating agents in the elderly AML, or in MDS patients who failed standard therapy, are all of special interest and currently ongoing. Another area of investigation is the combination of omacetaxine with the currently available TKIs in CML. One initial drawback to the use of omacetaxine was the restriction imposed by the FDA requiring that this agent be given exclusively in the healthcare setting, making the twicedaily injection schedule a significant challenge. This restriction has recently been lifted, and the FDA has now approved the use of omacetaxine for home injection [49]. This point requires special attention as the drug comes in single dose 3.5 mg vials, and the average drug given in CML was 2402
2.4 mg. Emphasis to avoid overdosing should take place when reviewing instructions with patients. Another general issue to consider when choosing the optimal drug for CML is the concern of overtreatment or undertreatment during the long-term clinical course of CML. An example of overtreatment is the aggressive therapeutic intervention during the CML management when a drug exhibits suboptimal response by proceeding onto ASCT when other drugs could be used effectively. On the other hand, undertreatment represents the phenomenon of insufficient intervention during the management when early signs of drug failure are noticed, resulting in disease progression and detrimental outcomes [57]. This is more relevant in the front-line setting and choice of TKIs per the European Leukemia Network recommendations. However, the concept could be projected and applied at the critical point upon the consideration of initiating omacetaxine; then again when observing lack or loss of response on omacetaxine. Pharmacoeconomy and cost are emerging as important factors in the choice of drugs in CML management. Omacetaxine is no exception of the expensive arsenal of CML drugs, with 28,000 $ as the cost of induction and 14,000 $ per maintenance course. The high cost of CML drugs, in general, is finally gaining more attention by the experts in the field to address its reasons and to propose solutions to reduce it to make these drugs more available to the affected patients [58].
Declaration of interest The paper was supported partially by grants from the National Cancer Institute Grant CA16056 (OA Ustwani, EA Griffiths, ES Wang, M Wetzler), the Cancer Clinical Investigator Team Leadership Award (CCITLA) awarded by the National Cancer Institute through a supplement to P30CA016056 (ES Wang), the Szefel Foundation, Roswell Park Cancer Institute, the Leonard S. LuVullo Endowment for Leukemia Research, the Nancy C. Cully Endowment for Leukemia Research, the
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Babcock Family Endowment and the Heidi Leukemia Research Fund, Buffalo, NY. M Wetzler was an investigator on the 202 and 203 studies, is a current investigator on other omacetaxine trials and served as a consultant for Teva. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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Affiliation Omar Al Ustwani MD, Elizabeth A Griffiths MD, Eunice S Wang MD & Meir Wetzler† MD † Author for correspondence Roswell Park Cancer Institute, Department of Medicine, Leukemia Section, Elm and Carlton Street, Buffalo, NY 14263, USA Tel: +001 716 845 8447; Fax: +001 716 845 2343; E-mail: [email protected]
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