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Review

Omacetaxine mepesuccinate in the treatment of intractable chronic myeloid leukemia

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Pages 177-186 | Published online: 31 Jan 2014

Abstract

In a significant proportion of patients with chronic myeloid leukemia, resistance to BCR-ABL tyrosine kinase inhibitors develops due to acquisition of BCR-ABL kinase domain mutations and insensitivity of leukemia stem cells to tyrosine kinase inhibitors. Omacetaxine mepesuccinate (formerly called homoharringtonine) is a natural alkaloid that inhibits protein synthesis and induces cell death. Omacetaxine mepesuccinate has been recently approved by the US Food and Drug Administration to treat patients with chronic myeloid leukemia who failed to respond to multiple tyrosine kinase inhibitors and/or acquired the BCR-ABL-T315I mutation. In this review, we discuss the use and effectiveness of omacetaxine mepesuccinate in the treatment of chronic myeloid leukemia, with coverage of its pharmacology, mode of action, and pharmacokinetics. We believe that omacetaxine mepesuccinate will be beneficial to many patients with chronic myeloid leukemia who do not respond well to tyrosine kinase inhibitors.

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative disease induced by the BCR-ABL oncogene. Pathologically, CML patients develop granulocytosis and splenomegaly. CML often begins with a chronic phase, and without proper treatment, the disease progresses to an accelerated phase and ultimately develops into a terminal phase called blast crisis. A hallmark of CML is acquisition of Philadelphia chromosome (Ph), resulting in formation of BCR-ABL.Citation1 The Ph chromosome is cytogenetically diagnostic of CML. In 1960, Nowell and Hungerford made a landmark discovery of the Ph chromosome and its association with CML.Citation1 This discovery was the first demonstration of a chromosomal rearrangement that is consistently linked to a specific cancer, and sparked searches for associations of additional chromosomal aberrations with specific forms of cancer. BCR-ABL, the product of the Ph chromosome, has deregulated tyrosine kinase activity, and different forms of BCR-ABL protein with different molecular weights can be generated in patients, depending on the precise breakpoints in the translocation or RNA splicing.Citation2 The BCR-ABL transcript was shown to contain the first 13 to 14 BCR exons and exons 1 or 2 through 11 of ABL, generating a large mRNA product that, after splicing, encoded an 8.5 kB BCR-ABL chimeric transcript.Citation3 The fusion of BCR to ABL during translocation increases the tyrosine kinase activity of ABL, and brings new regulatory domains/motifs to ABL, such as the growth factor receptor-bound protein 2 SH2-binding sites.Citation4Citation6

CML in accelerated phase and blast crisis is much more diverse and aggressive than chronic phase CML. Over 80% of patients in blast phase have definable genetic aberrations in addition to the Ph chromosome.Citation7 Those genetic aberrations including trisomy 8, i(17q),Citation7,Citation8 loss of p53 function,Citation9,Citation10 MYC amplification,Citation8 RB deletion/rearrangement,Citation11 and p16INK4A (CDKN2) rearrangement/deletionCitation12 have been reported to be associated with blast crisis.

Treatment of CML

Before BCR-ABL tyrosine kinase inhibitors (TKIs) were available, allogeneic bone marrow transplantation was the recommended treatment for patients newly diagnosed with CML. The probability of survival and leukemia-free survival of bone marrow transplant recipients at 8 years was 50%–60%, with a low chance of relapse.Citation13,Citation14 After receiving bone marrow transplantation, the majority of long-term survivors could be regarded as operationally “cured”, even if some patients still harbored quiescent leukemia cells.Citation15 In 2001, the first BCR-ABL kinase inhibitor, imatinib mesylate (Gleevec®/Glivec®, formerly STI571; Novartis, Basel, Switzerland), was approved by the US Food and Drug Administration as a first-line standard treatment for CML.Citation16Citation18 The rate of complete cytogenetic response among patients receiving imatinib was 87% after 5 years of treatment.Citation19 Although it effectively inhibits BCR-ABL kinase activity and improves survival in CML patients, imatinib does not appear to lead to a cure of the disease due to development of point mutations in the ATP binding region of BCR-ABL and the insensitivity of quiescent leukemic stem cells to imatinib. Acquisition of point mutations in the ATP binding region of BCR-ABL has been a major mechanism for development of resistance to imatinib and other BCR-ABL kinase inhibitors. BCR-ABL gene amplification also leads to increased expression of BCR-ABL tyrosine kinase and is associated with drug resistance.Citation20 BCR-ABL-independent resistance mechanisms include effects on drug efflux, import, and binding.Citation21 Further, variations in compound intracellular uptake and retention affect efficacy differences in patients.Citation22 For example, three BCR-ABL mutations (T315I, Y253H, and F317L) have a predicted role in abrogating binding of imatinib to BCR-ABL in resistant patients.Citation23 The second-generation BCR-ABL kinase inhibitor, dasatinib, binds to BCR-ABL with less stringent conformational requirements and was shown to be effective in inhibition of imatinib-resistant mutants.Citation24 Nilotinib is another second-generation BCR-ABL inhibitor and is significantly more potent than imatinib, and also has activity against a number of imatinib-resistant BCR-ABL mutants.Citation25 Compared with imatinib, nilotinib is associated with a reduced incidence of BCR-ABL mutations in patients with newly diagnosed CML in chronic phase.Citation26 Based on a 3-year study, mutations were detected in approximately twice as many patients on imatinib (400 mg once daily) as on nilotinib (300 mg twice daily or 400 mg twice daily).Citation26 Recently, ponatinib, a third-generation TKI, was approved and demonstrated to have remarkable antileukemia activity, particularly in patients with BCR-ABL-T315I mutations that are resistant to other TKIs.Citation27 Ponatinib is a powerful pan-BCR-ABL TKI and is promising for patients with CML or Ph+ acute lymphoblastic leukemia who fail imatinib, dasatinib, and nilotinib.Citation20 It is also active against T315I and other imatinib-resistant mutants.Citation20 However, not all CML patients who are refractory or intolerant to dasatinib or nilotinib are responsive to ponatinib.Citation20 Besides the development of TKI resistance, it has been shown that survival of primitive CML stem cells is not dependent on BCR-ABL kinase activity, and as a result, therapies that aim to inhibit BCR-ABL kinase activity could not eliminate leukemia stem cells in CML.Citation28Citation31 Thus, a significant number of CML patients will take TKIs for the rest of their lives.Citation32 We have shown that the resistance of leukemia stem cells to imatinib does not appear to involve BCR-ABL kinase domain mutations,Citation33 suggesting that BCR-ABL activates some signaling pathways in a kinase-independent manner in leukemia stem cells.Citation15 Some unique molecular pathways dependent on or independent of BCR-ABL kinase activity were identified to play important roles in the development and survival of leukemia stem cells in CML, including Wnt/β-catenin, Hedgehog, Alox5, PTEN, Src family kinases, and FoxO pathways.Citation33Citation38 These newly identified genes may serve as potential targets for developing a curative therapy of CML.

Omacetaxine mepesuccinate was recently approved by the US Food and Drug Administration for treating CML patients with resistance or intolerance to two or more TKIs. It is a first-in-class cephalotaxine that has demonstrated efficacy in CML and was shown to produce clinically meaningful responses with acceptable tolerability in patients with chronic phase CML previously treated with two or more TKIs.Citation39 In this paper, we discuss the pharmacology, mode of action, and pharmacokinetics of omacetaxine mepesuccinate, efficacy studies in both patients and animal models of CML, and the safety and tolerability of omacetaxine mepesuccinate as well as its future perspectives.

Pharmacology, mode of action, and pharmacokinetics

Pharmacology

Omacetaxine mepesuccinate is also known as homohar ringtonine (HHT) [cephalotaxine, 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester)]. It is a natural cephalotaxine alkaloid (), and is originally derived from the bark of several cephalotaxus species that are indigenous to Asia (mostly mainland China, and also Japan, Korea, and India).Citation40 The molecular weight of omacetaxine mepesuccinate is 545.62 (g/mol).Citation40 Historically, extracts from the bark of cephalotaxus were used in cancer patients by practitioners of traditional Chinese medicine in the Fujian Province of China.Citation41 However, further development of HHT was hampered by a limited source supply and difficult production for high purity. The successful semisynthesis of HHT by direct esterification of the abundant biosynthetic precursor cephalotaxine was reported in 1999. The development of semisynthetic HHT was paralleled by development of the more convenient subcutaneous route of administration, with pharmacokinetic properties, clinical efficacy, and safety comparable with that of continuous infusion. Semisynthetic HHT is now produced as omacetaxine mepesuccinate (Synribo®, Teva Pharmaceutical Industries Ltd, Petah Tikva, Israel). It is worth mentioning that omacetaxine mepesuccinate is the only effective natural therapeutic agent used in patients with CML.

Figure 1 The structure of omacetaxine mepesuccinate.

Notes: Drug name: omacetaxine mepesuccinate (SYNRIBO); Indication: Adult patients with CMP-CP or AP with resistance and/or intolerance to two or more TKIs; Chemical structure: 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester).
Abbreviations: CMP-CP, common myeloid progenitor-chronic phase; AP, accelerated phase; TKI, tyrosine kinase inhibitor.
Figure 1 The structure of omacetaxine mepesuccinate.

Mode of action

Omacetaxine mepesuccinate functions as an inhibitor of protein synthesis, mechanistically preventing aminoacyl-tRNA binding to the ribosomal acceptor site and peptide bond formation at the early stage of protein elongation.Citation41,Citation42 elongation phase of translation by preventing substrate binding to the acceptor site on the 60-S ribosome subunit, leading to blockade of aminoacyl-tRNA binding and peptide bond formation.Citation42 Further, omacetaxine mepesuccinate was shown to affect diphenylalanine synthesis and puromycin reaction instead of eEF-1-dependent Phe-tRNAPhe binding, and to exert a significant influence on polypeptide chain elongation.Citation43,Citation44 A recent study showed that omacetaxine mepesuccinate blocks protein synthesis by competing with the amino acid side chains of incoming aminoacyl-tRNAs for binding at the A-site cleft in the peptidyl transferase center.Citation45

The mechanism for the antileukemic effect of omacetaxine mepesuccinate is mainly related to induction of apoptosis in leukemia cells ().Citation46 In imatinib-resistant K562 cells, omacetaxine mepesuccinate caused degradation of BCR-ABL proteins by inhibiting heat shock protein 90 in a dose-dependent manner,Citation47 whereas heat shock protein 70, which mediates the resistance of BCR-ABL-expressing cells to apoptosis, was not changed by treatment with the drug. Omacetaxine mepesuccinate also induced intrinsically apoptotic pathways by activating caspase-9, caspase-8, and caspase-3 and downregulating myeloid cell leukemia-1 (MCL-1) in chronic lymphocytic leukemiaCitation48 and in myeloid leukemia cells.Citation49 Although downregulation of MCL-1 was associated with a substantial decrease in viability of K562 cells, loss of MCL-1 did not significantly enhance the efficacy of omacetaxine mepesuccinate in primary B-cells or neutrophils.Citation48 In BCR-ABL-induced B-cell acute lymphoblastic leukemia, treatment with omacetaxine mepesuccinate slightly reduced the level of nonmutated BCR-ABL proteins, but the level of BCR-ABL-T315I was markedly decreased, indicating that the mutant BCR-ABL is more sensitive to inhibition by omacetaxine mepesuccinate.Citation47 Interestingly, compared with myeloid leukemia cells, the level of heat shock protein 90 in B-cell acute lymphoblastic leukemia cells was not reduced by treatment with omacetaxine mepesuccinate. The stability of the BCR-ABL-T315I mutant may be more sensitive to treatment with omacetaxine mepesuccinate and depends on alternative oncoprotein chaperones, such as heat shock protein 70 or Hsc70.

Figure 2 The major mechanism of action of omacetaxine mepesuccinate.

Abbreviations: WT, wild type, CML, chronic myeloid leukemia; MCL-1, myeloid cell leukemia-1.
Figure 2 The major mechanism of action of omacetaxine mepesuccinate.

Omacetaxine mepesuccinate also had a significant inhibitory effect on leukemia stem cells. In a mouse model of CML, omacetaxine mepesuccinate was shown to greatly reduce the numbers of both leukemia stem cells and total leukemia cells, and treatment of CML mice using both imatinib and omacetaxine mepesuccinate did not further reduce the number of leukemia stem cells or total leukemia cells compared with mice treated using omacetaxine mepesuccinate alone.Citation47 Omacetaxine mepesuccinate also had a similar inhibitory effect on BCR-ABL T315I-expressing leukemia stem cells compared with nonmutant BCR-ABL-expressing leukemia stem cells. On the other hand, when samples from patients with primary CML were tested, omacetaxine mepesuccinate effectively induced apoptosis of primary human CML stem cells (CD34+38low) by downregulation of MCL-1 proteins.Citation50 In contrast with findings for TKIs, omacetaxine mepesuccinate did not cause accumulation of undivided cells in vitro. Further, the functions of surviving stem cells following treatment with omacetaxine mepesuccinate was significantly reduced in a dose-dependent manner, as determined by a colony-forming assay and the more stringent long-term culture-initiating cell colony assay.Citation50

The cytotoxicity of omacetaxine mepesuccinate was thought to be caused by inhibition of cells in the G1 and G2 phasesCitation42 or differentiated noncycling cells,Citation51 and through reduction in levels of pro-oncogenic or prosurvival proteins through shortening their half-lives, including those of MCL-1, cyclin D1, and c-MYC.Citation52 Although more mechanistic studies are needed to understand fully the molecular mechanisms by which omacetaxine mepesuccinate suppresses CML cells, the various studies described above have consistently shown that MCL-1 is involved in inhibition of CML cells by omacetaxine mepesuccinate. Identification of other signaling pathways that interact with MCL-1 in CML cells is a logical next step to take in better understanding the mode of action of omacetaxine mepesuccinate.

Pharmacokinetics

Omacetaxine mepesuccinate is administered subcutaneously, and maximum concentration in blood is achieved within one hour of injection.Citation53 Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT through plasma esterases with hepatic microsomal oxidative and/or esterase-mediated metabolism.Citation53 On average, less than 15% of omacetaxine mepesuccinate is excreted unchanged in the urine, and its mean half-life following subcutaneous administration is around 6 hours.Citation53 To understand its pharmacokinetics, omacetaxine mepesuccinate (1.25 mg/m2) was administered subcutaneously twice a day on days 1–14 every 28 days for two cycles, until disease progression or unacceptable toxicity occurred. Blood and urine were collected to measure concentrations of omacetaxine mepesuccinate and its inactive metabolites. Pharmacokinetic parameters were estimated from 21 patients with a diagnosis of relapsed or refractory CML, acute promyelocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome, or advanced solid tumors who had exhausted or become intolerant to all available therapies.Citation53 Omacetaxine mepesuccinate is rapidly absorbed and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m.Citation53 Plasma concentration versus time data demonstrated biexponential decay and a mean steady-state terminal half-life of 7 hours. Concentrations of inactive metabolites, 4′-DMHHT and cephalotaxine, were approximately 10% those of omacetaxine mepesuccinate and undetectable in most patients.Citation53

The clinical pharmacokinetics of omacetaxine mepesuccinate was similarly studied in eight patients who received uniformly labeled omacetaxine mepesuccinate at 3–4 mg/m2 by continuous 6-hour infusion.Citation54 Unchanged omacetaxine mepesuccinate declined biphasically in plasma, with an α-half-life of 0.5±0.1 hours and a β-half-life of 9.3±1.4 hours. The total clearance of omacetaxine mepesuccinate was 177.4±27.7 mL/hour × kg, and the apparent volume of distribution, estimated from the area under the drug concentration versus time curve, was 2.4±0.4 L/kg.Citation54

Omacetaxine mepesuccinate is mainly metabolized in the liver, but does not cause clinical liver toxicity.Citation55 A major metabolite of omacetaxine mepesuccinate was identified as omacetaxine mepesuccinate acid, which was 700 times less toxic than omacetaxine mepesuccinate. Urinary excretion of unchanged omacetaxine mepesuccinate accounted for 15% of the dose.Citation55 The major drug-related adverse effects included thrombocytopenia (48%) and neutropenia (33%).Citation55 Although omacetaxine mepesuccinate appears to have more side effects than TKIs, it has a unique activity against TKI-insensitive CML stem cells (see below), making it a useful therapeutic agent in some patients who have failed to respond to TKIs.

Efficacy studies

Efficacy of omacetaxine mepesuccinate in treating CML

Omacetaxine mepesuccinate has been studied using BCR-ABL-expressing myeloid and lymphoid cell lines and mouse models of CML and B-cell acute lymphoblastic leukemia induced by nonmutant BCR-ABL or mutant BCR-ABL-T315I.Citation47 It is exciting to see that more than 90% of leukemia stem cells are killed after treatment with omacetaxine mepesuccinate in vitro. Omacetaxine mepesuccinate effectively caused reduction of leukemia cells in CML and mice with B-cell acute lymphoblastic leukemia.Citation47 Omacetaxine mepesuccinate also inhibited BCR-ABL T315I-expressing leukemia stem cells.Citation47

Omacetaxine mepesuccinate was initially used in the early 1980s to treat CML patients in the People’s Republic of China,Citation56 and two clinical studies later showed that omacetaxine mepesuccinate was an effective treatment for CML, as shown by induction of hematologic remission for longer than 12 months in the majority of patients in chronic phase.Citation57,Citation58 In a Phase I/II study of subcutaneous administration of omacetaxine mepesuccinate in CML patients who had failed prior therapy, efficacy and good tolerance were observed for omacetaxine mepesuccinate, and could be achieved when the same doses were administered by intravenous injection.Citation59 The maximal tolerated dose was 1.25 mg/m2 subcutaneously twice daily. Six patients (median age 53 years) who had failed imatinib were treated with omacetaxine mepesuccinate, and five turned out to be evaluable.Citation59 Among the five patients, a complete hematologic response (CHR) was achieved in all patients and three patients had a cytogenetic response (one complete and two minor).Citation59 In two patients who were found to have BCR-ABL kinase domain mutations at the start of treatment with omacetaxine mepesuccinate, a cytogenetic response were achieved and accompanied by no detectable BCR-ABL mutations.Citation60 The efficacy of omacetaxine mepesuccinate was assessed further in a Phase II study of CML patients with the BCR-ABL-T315I mutation.Citation61 In total, 62 patients received a median of seven cycles of omacetaxine mepesuccinate. A CHR was achieved in 48 of these patients and their median response duration was 9.1 months. Fourteen patients achieved a major cytogenetic response, including a complete cytogenetic response in ten patients (16%). Median progression free-survival in this trial was 7.7 months.

So far, a couple of Phase II studies have been conducted to test HHT/omacetaxine mepesuccinate either alone or in combination with other antitumor agents in 828 CML patients with different disease stages ( and ). Four single-agent Phase II studies tested the effect of HHT/omacetaxine mepesuccinate in early or late chronic phase CML patients.Citation57,Citation58,Citation60,Citation62 In total, 212 CML patients were treated with HHT (2.5 mg/m2 ×14 days) or omacetaxine mepesuccinate (1.25 mg/m2 twice/day ×14 days). The average CHR was 80%, and 42% of patients achieved a cytogenetic response. Four single-agent Phase II studies demonstrated the effectiveness of omacetaxine mepesuccinate in treating CML patients resistant or intolerant to two or more TKIs.Citation63Citation66 A total of 252 CML patients were treated with omacetaxine mepesuccinate (1.25 mg/m2 twice daily, 28 days cycle for induction, ≤7 days/cycle as maintenance), and the average cytogenetic response rate was 20.5%.

Table 1 Summary of OM related clinic trials

Table 2 Summary of current CML treatment

Omacetaxine mepesuccinate were also tested in combination with other active agents. Two Phase II trials tested the efficacy of omacetaxine mepesuccinate (1.25 mg/m2 twice daily ×14 days) combined with imatinib in 24 patients with chronic phase CML.Citation59,Citation67 The average CHR of drug-treated patients was 66%. Fifty percent of these patients achieved a cytogenetic response. Four Phase II trials tested the effect of a combination of HHT 2.5 mg/m2 and ara-C in 202 patients with chronic phase CML.Citation68,Citation69 The average CHR was 81%. One Phase II trial tested the effect of HHT 2.5 mg/m2 combined with interferon-α in 37 patients with early chronic phase CML.Citation70 The average CHR was 89%, with 57% of patients achieving a cytogenetic response. One Phase II trial tested the effect of omacetaxine mepesuccinate combined with imatinib and granulocyte colony-stimulating factor in eleven patients with blast phase CML.Citation71 The average CHR was 61%, and 100% of patients achieved a cytogenetic response. Another Phase II trial tested the effect of a combination of HHT, interferon-α, and ara-C in 90 patients with early chronic phase CML.Citation72 The average CHR was 94%, and 74% of patients achieved a cytogenetic response.

Efficacy of omacetaxine mepesuccinate in other blood malignancies

In addition to being used to treat CML, omacetaxine mepesuccinate has also been used to treat other types of blood malignancy, such as myelodysplastic syndrome, acute myeloid leukemia, and multiple myeloma. Although CML is the focus of this review, we believe that it would be beneficial if we also discuss, at least briefly, other diseases in which omacetaxine mepesuccinate has a therapeutic effect.

In a study using HHT at a dose of 5 mg/m2 by 24-hour continuous infusion for 9 days in 28 patients (16 with myelodysplastic syndrome, 12 with myelodysplastic syndrome/acute myeloid leukemia), a 28% overall response rate (8/28) was achieved, with complete remission in seven patients and partial remission in one patient.Citation73 In another Phase II pilot study of HHT in myelodysplastic syndrome, HHT was given at a dose of 2.5 mg/m2 via continuous infusion for 7 days and maintenance every 4 weeks. One patient (11%) responded with a CHR and cytogenetic remission after one course and eight patients did not respond.Citation74 Similarly, the effect of omacetaxine mepesuccinate was tested in patients with acute myeloid leukemia. HHT was evaluated at a dose of 5 mg/m2 by continuous infusion daily for 9 days in 66 patients with relapsed/refractory acute myeloid leukemia or blastic phase CML. Seven of 43 patients with relapsed acute myeloid leukemia achieved a complete remission (16%). Two of three patients primarily resistant to low-dose cytarabine also achieved complete remission, while eleven patients with acute myeloid leukemia primarily resistant to an anthracycline-cytarabine combination did not respond.Citation75 The effect of omacetaxine mepesuccinate was also shown to have a stronger effect on acute myeloid leukemia when combined with other therapeutic agents such as cytarabine, aclarubicin, or granulocyte-colony stimulating factor.Citation76Citation78

The efficacy of omacetaxine mepesuccinate was also studied in multiple myeloma. Omacetaxine mepesuccinate significantly inhibited proliferation of human multiple myeloma cell lines and tumor cells from patients with relapsed refractory multiple myeloma in a dose-dependent manner.Citation79 Omacetaxine mepesuccinate further reduced the levels of cellular FLICE-like inhibitory protein, activated caspase-8, and induced active truncated-Bid in multiple myeloma cells, including RPMI8226 and U266.Citation79 When combined with other antitumor agents, omacetaxine mepesuccinate enhanced the efficacy of melphalan, bortezomib, and ABT-737.Citation80 The cytotoxicity of omacetaxine mepesuccinate was related to downregulation of AKT phosphorylation/activation and various substrates of AKT, including nuclear factor kappa B, XIAP, cIAP, and cyclin D1.Citation81

Safety and tolerability

Myelosuppression and nonhematologic toxicity

Myelosuppression is a major dose-related side effect of omacetaxine mepesuccinate. In CML patients treated with omacetaxine mepesuccinate alone or in combination with TKIs or other agents, intravenous administration of omacetaxine mepesuccinate caused granulocytopenia (<0.5×109/L) in 27%–39% of patients, and thrombocytopenia (30×109/L) in 13%–25% of patients.Citation57,Citation58 Myelosuppression is also the principal side effect with subcutaneous administration of omacetaxine mepesuccinate.Citation39

The most common nonhematologic toxicities in CML patients treated with omacetaxine mepesuccinate include diarrhea, fatigue, pyrexia, nausea, asthenia, headache, anorexia, hyperglycemia, injection site erythema, and tachycardia/chest pain.Citation59,Citation60,Citation82Citation84 Recently, a pooled safety analysis in patients with TKI-resistant CML treated using subcutaneous omacetaxine mepesuccinate (1.25 mg/m2) showed an acceptable safety profile in all phases of CML.Citation85 Adverse events were primarily hematologic, and grade 3/4 nonhematologic adverse events were uncommon.Citation85 However, a concern is the potential adverse effects in patients after long-term use of omacetaxine mepesuccinate. It is likely that some patients may not tolerate these adverse effects, and need to switch to other therapies. On the other hand, some patients may benefit from this treatment, simply because they have run out of therapeutic options and the drug is effective. Further, in contrast with TKIs, omacetaxine mepesuccinate has an inhibitory activity against leukemia stem cells, making it an attractive therapy for being close to curing the disease.

Potential use of omacetaxine mepesuccinate

Imatinib at 400 mg daily is the standard of care for patients with CML in chronic phase, and dasatinib and nilotinib represent alternatives that have replaced imatinib as first-line therapy in patients with imatinib resistance or intolerance.Citation19,Citation86Citation88 Clearly, omacetaxine mepesuccinate will not substitute for imatinib and other TKIs. However, omacetaxine mepesuccinate has a unique role in certain patients with CML. First, because omacetaxine mepesuccinate primarily targets signaling molecules downstream of BCR-ABL and has a unique mode of action, it could be a choice for patients carrying BCR-ABL mutation and resistant to TKIs, because some patients including BCR-ABL-T315I carriers do not respond to available TKIs. For these patients, omacetaxine mepesuccinate could be used as a single agent for treating CML. Second, TKIs do not eradicate the leukemia stem cells that initiate CML. Finally, omacetaxine mepesuccinate has been shown to have an inhibitory effect on leukemia stem cells in preclinical models.Citation47,Citation50 Therefore, omacetaxine mepesuccinate should be used in combination with a TKI. A recent study showed that omacetaxine mepesuccinate in combination with nilotinib led to undetectable residual disease at a molecular level in an imatinib-resistant CML patient harboring the BCR-ABL-T315I mutation.Citation89 As the third-generation TKI ponatinib came to the market and responses were observed in highly refractory patients with either no mutations or other mutations resistant to first- or second-generation FDA approved TKIs.Citation20 Thus, a combinatorial therapeutic strategy using omacetaxine mepesuccinate and a new-generation TKI would be an attractive approach in helping to cure CML. In fact, omacetaxine mepesuccinate has been shown to be effective in treating CML as a single agentCitation57,Citation58,Citation60,Citation62 and in combination with imatinib,Citation58,Citation90 interferon-α,Citation70 cytarabine,Citation68,Citation69 and both interferon-α and cytarabine.Citation72

Conclusion

After the US Food and Drug Administration granted accelerated approval for omacetaxine mepesuccinate (Synribo) in the treatment of adult patients in CML chronic phase or accelerated phase with resistance and/or intolerance to two or more TKIs, its effectiveness in treating these patients has been observed. In addition, omacetaxine mepesuccinate has been shown to have inhibitory activity in TKI-insensitive CML stem cells, suggesting that this agent in combination with TKIs provides a curative therapeutic strategy for CML patients.

Disclosure

The authors report no conflicts of interest in this work.

References

  • NowellPCHungerfordDAChromosome studies in human leukemia. IV. Myeloproliferative syndrome and other atypical myeloid disordersJ Natl Cancer Inst19622991193113939164
  • LiSIlariaRLJrMillionRPDaleyGQVan EttenRAThe P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activityJ Exp Med19991891399141210224280
  • MeloJVThe diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotypeBlood199688237523848839828
  • PendergastAMQuilliamLACripeLDBCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor proteinCell1993751751858402896
  • GrossAWZhangXRenRBcr-Abl with an SH3 deletion retains the ability to induce a myeloproliferative disease in mice, yet c-Abl activated by an SH3 deletion induces only lymphoid malignancyMol Cell Biol1999196918692810490629
  • GhaffariSDaleyGQLodishHFGrowth factor independence and BCR/ABL transformation: promise and pitfalls of murine model systems and assaysLeukemia1999131200120610450747
  • MitelmanFThe cytogenetic scenario of chronic myeloid leukemiaLeuk Lymphoma199311Suppl 111158251885
  • JenningsBAMillsKIc-MYC locus amplification and the acquisition of trisomy 8 in the evolution of chronic myeloid leukaemiaLeuk Res1998228999039766750
  • ProkocimerMRotterVStructure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineagesBlood199484239124117919359
  • FeinsteinECiminoGGaleRPp53 in chronic myelogenous leukemia in acute phaseProc Natl Acad Sci U S A199188629362972068108
  • AhujaHGJatPSFotiABar-EliMClineMJAbnormalities of the retinoblastoma gene in the pathogenesis of acute leukemiaBlood199178325932681683797
  • SillHGoldmanJMCrossNCHomozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemiaBlood199585201320167718873
  • MughalTIYongASzydloRMMolecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapseBr J Haematol200111556957411736937
  • van RheeFSzydloRMHermansJLong-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow TransplantationBone Marrow Transplant1997205535609337056
  • ChenYPengCSullivanCLiDLiSCritical molecular pathways in cancer stem cells of chronic myeloid leukemiaLeukemia2010241545155420574455
  • DrukerBJChronic myeloid leukemia. Sceptical scientistsLancet2001358SupplS1111784560
  • MauroMJDrukerBJSTI571: a gene product-targeted therapy for leukemiaCurr Oncol Rep2001322322711296132
  • DrukerBJSawyersCLKantarjianHActivity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosomeN Engl J Med20013441038104211287973
  • DrukerBJGuilhotFO’BrienSGFive-year follow-up of patients receiving imatinib for chronic myeloid leukemiaN Engl J Med20063552408241717151364
  • OhanianMCortesJKantarjianHJabbourETyrosine kinase inhibitors in acute and chronic leukemiasExpert Opin Pharmacother20121392793822519766
  • BixbyDTalpazMMechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistanceHematology Am Soc Hematol Educ Program200946147620008232
  • WhiteDLSaundersVADangPOCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinibBlood200610869770416597591
  • BranfordSRudzkiZWalshSHigh frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistanceBlood2002993472347511964322
  • ShahNPTranCLeeFYChenPNorrisDSawyersCLOverriding imatinib resistance with a novel ABL kinase inhibitorScience200430539940115256671
  • WeisbergEManleyPWBreitensteinWCharacterization of AMN107, a selective inhibitor of native and mutant Bcr-AblCancer Cell2005712914115710326
  • HochhausASaglioGLarsonRANilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phaseBlood20131213703370823502220
  • FrankfurtOLichtJDPonatinib – a step forward in overcoming resistance in chronic myeloid leukemiaClin Cancer Res2013195828583423935038
  • HamiltonAHelgasonGVSchemionekMChronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survivalBlood20121191501151022184410
  • HolyoakeTJiangXEavesCEavesAIsolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemiaBlood1999942056206410477735
  • GrahamSMJorgensenHGAllanEPrimitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitroBlood20029931932511756187
  • CorbinASAgarwalALoriauxMCortesJDeiningerMWDrukerBJHuman chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activityJ Clin Invest201112139640921157039
  • RousselotPHuguetFReaDImatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 yearsBlood2007109586016973963
  • HuYChenYDouglasLLiSBeta-catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemiaLeukemia20092310911618818703
  • ZhaoCBlumJChenALoss of beta-catenin impairs the renewal of normal and CML stem cells in vivoCancer Cell20071252854118068630
  • NakaKHoshiiTMuraguchiTTGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemiaNature201046367668020130650
  • ZhaoCChenAJamiesonCHHedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemiaNature200945877677919169242
  • PengCChenYYangZPTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in miceBlood201011562663519965668
  • ChenYHuYZhangHPengCLiSLoss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemiaNat Genet20094178379219503090
  • CortesJENicoliniFEWetzlerMSubcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinibClin Lymphoma Myeloma Leuk20131358459123787123
  • KimTDFrickMle CoutrePOmacetaxine mepesuccinate for the treatment of leukemiaExpert Opin Pharmacother2011122381239221916787
  • HuangMTHarringtonine, an inhibitor of initiation of protein biosynthesisMol Pharmacol1975115115191237080
  • FresnoMJimenezAVazquezDInhibition of translation in eukaryotic systems by harringtonineEur J Biochem197772323330319998
  • TujebajevaRMGraiferDMKarpovaGGAjtkhozhinaNAAlkaloid homoharringtonine inhibits polypeptide chain elongation on human ribosomes on the step of peptide bond formationFEBS Lett19892572542562583270
  • TujebajevaRMGraiferDMMatasovaNBSelective inhibition of the polypeptide chain elongation in eukaryotic cellsBiochim Biophys Acta199211291771821730056
  • GurelGBlahaGMoorePBSteitzTAU2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosomeJ Mol Biol200938914615619362093
  • WetzlerMSegalDOmacetaxine as an anticancer therapeutic: what is old is new againCurr Pharm Des201117596421294709
  • ChenYHuYMichaelsSSegalDBrownDLiSInhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in miceLeukemia2009231446145419322212
  • ChenRGuoLChenYJiangYWierdaWGPlunkettWHomoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemiaBlood201111715616420971952
  • TangRFaussatAMMajdakPSemisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cellsMol Cancer Ther2006572373116546987
  • AllanEKHolyoakeTLCraigARJorgensenHGOmacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cellsLeukemia20112598599421468038
  • LindqvistLMVikstromIChambersJMTranslation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributorCell Death Dis20123e40923059828
  • RobertFCarrierMRaweSChenSLoweSPelletierJAltering chemosensitivity by modulating translation elongationPLoS One20094e542819412536
  • NemunaitisJMitaAStephensonJPharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumorsCancer Chemother Pharmacol201371354123053254
  • SavarajNLuKDimeryIClinical pharmacology of homoharringtonineCancer Treat Rep198670140314073791253
  • NiDHoDHVijjeswarapuMFelixERheaPRNewmanRAMetabolism of homoharringtonine, a cytotoxic component of the evergreen plant Cephalotaxus harringtoniaJ Exp Ther Oncol20033475212724858
  • ZhangZYHouCHZhuYFA preliminary therapeutic analysis of 82 cases of chronic granulocytic leukemia treated with harringtonineZhonghua Nei Ke Za Zhi198625156157190 Chinese3461929
  • O’BrienSKantarjianHKeatingMHomoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phaseBlood199586332233267579434
  • O’BrienSKantarjianHKollerCSequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemiaBlood1999934149415310361112
  • MarinDKaedaJSAndreassonCPhase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinibCancer20051031850185515786422
  • Quintas-CardamaAKantarjianHGarcia-ManeroGPhase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapyCancer200710924825517154172
  • CortesJLiptonJHReaDPhase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutationBlood20121202573258022896000
  • CortesJDigumartiRParikhPMPhase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitorsAm J Hematol20138835035423468307
  • NicoliniFE LJKantarjianHSubcutaneous omacetaxine mepesuccinate in patients with chronic phase (CP) or accelerated phase (AP) chron myeloid leukemia (CML) resistant/intolerant to two or three approved tyrosine-kinase inhibitors (TKIs)ASCO Annual Meeting2012306513
  • NicoliniFEKhouryHJAkardLOmacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitorsHaematologica2013987e78e7923753022
  • NicoliniFEChomelJCRoyLThe durable clearance of the T315I BCR-ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallengeClin Lymphoma Myeloma Leuk20101039439921030353
  • AkardLP KHNicoliniFEOmacetaxine mepesuccinate in chronic-phase chronic myeloid leukemia (CML) in patients resistant, intolerant, or both to two or more tyrosine-kinase inhibitors (TKIs)ASCO Annual Meeting2012306596
  • LiYFLiuXLiuDSDinBHZhuJBThe effect of homoharringtonine in patients with chronic myeloid leukemia who have failed or responded suboptimally to imatinib therapyLeuk Lymphoma2009501889189119860613
  • KantarjianHMTalpazMSmithTLHomoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemiaJ Clin Oncol2000183513352111032593
  • StoneRMDonohueKAStockWA phase II study of continuous infusion homoharringtonine and cytarabine in newly diagnosed patients with chronic myeloid leukemia: CALGB study 19804Cancer Chemother Pharmacol20096385986418670778
  • O’BrienSTalpazMCortesJSimultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemiaCancer2002942024203211932905
  • FangBLiNSongYHanQZhaoRCStandard-dose imatinib plus low-dose homoharringtonine and granulocyte colony-stimulating factor is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imatinibAnn Hematol2010891099110520499235
  • O’BrienSGilesFTalpazMResults of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phaseCancer20039888889312942553
  • FeldmanEJSeiterKPAhmedTBaskindPArlinZAHomoharringtonine in patients with myelodysplastic syndrome (MDS) and MDS evolving to acute myeloid leukemiaLeukemia19961040428558935
  • DaverNVega-RuizAKantarjianHMA phase II open-label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndromeEur J Cancer Care (Engl)20132260561123701251
  • FeldmanEArlinZAhmedTHomoharringtonine in combination with cytarabine for patients with acute myelogenous leukemiaLeukemia19926118911911434803
  • ZhangWGWangFXChenYXCombination chemotherapy with low-dose cytarabine, homoharringtonine, and granulocyte colony-stimulating factor priming in patients with relapsed or refractory acute myeloid leukemiaAm J Hematol20088318518817899614
  • WuLLiXSuJEffect of low-dose cytarabine, homoharringtonine and granulocyte colony-stimulating factor priming regimen on patients with advanced myelodysplastic syndrome or acute myeloid leukemia transformed from myelodysplastic syndromeLeuk Lymphoma2009501461146719672772
  • YuWMaoLQianJHomoharringtonine in combination with cytarabine and aclarubicin in the treatment of refractory/relapsed acute myeloid leukemia: a single-center experienceAnn Hematol2013921091110023595277
  • LouYJQianWBJinJHomoharringtonine induces apoptosis and growth arrest in human myeloma cellsLeuk Lymphoma2007481400140617613769
  • KurodaJKamitsujiYKimuraSAnti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-cateninInt J Hematol20088750751518415656
  • MengHYangCJinJZhouYQianWHomoharringtonine inhibits the AKT pathway and induces in vitro and in vivo cytotoxicity in human multiple myeloma cellsLeuk Lymphoma2008491954196218949618
  • LevyVZoharSBardinCA phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemiaBr J Cancer20069525325916847470
  • KantarjianHMKeatingMJWaltersRSKollerCAMcCredieKBFreireichEJPhase II study of low-dose continuous infusion homoharringtonine in refractory acute myelogenous leukemiaCancer1989638138172914287
  • SylvesterRKLobellMOgdenWStewartJAHomoharringtonine-induced hyperglycemiaJ Clin Oncol198973923952645387
  • WetzlerMKantarjianHNicoliniFEPooled safety analysis of omacetaxine mepesuccinate in patients with chronic myeloid leukemia (CML) resistant to tyrosine-kinase inhibitors (TKIs)J Clin Oncol201230Suppl Abstr 6604
  • KantarjianHShahNPHochhausADasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemiaN Engl J Med20103622260227020525995
  • NicoliniFETurkinaAShenZXExpanding Nilotinib Access in Clinical Trials (ENACT): an open-label, multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phaseCancer201211811812621732337
  • Koren-MichowitzMle CoutrePDuysterJActivity and tolerability of nilotinib: a retrospective multicenter analysis of chronic myeloid leukemia patients who are imatinib resistant or intolerantCancer20101164564457220572041
  • CoudeMMLuycxOCariouMEUndetectable molecular residual disease after omacetaxine and nilotinib combination therapy in an imatinib-resistant chronic myeloid leukaemia patient harbouring the BCR-ABL1 T315I gatekeeper mutationBr J Haematol201215740741022225474
  • LiYFDengZKXuanHBProlonged chronic phase in chronic myelogenous leukemia after homoharringtonine therapyChin Med J (Engl)20091221413141719567163