Homoharringtonine and omacetaxine for myeloid hematological malignancies
© Lü and Wang; licensee BioMed Central Ltd. 2014
Received: 8 November 2013
Accepted: 26 December 2013
Published: 3 January 2014
Homoharringtonine (HHT), a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action by preventing the initial elongation step of protein synthesis. HHT has been used widely in China for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Omacetaxine, a semisynthetic form of HHT, with excellent bioavailability by the subcutaneous route, has recently been approved by FDA of the United States for the treatment of CML refractory to tyrosine kinase inhibitors. This review summarized preclinical and clinical development of HHT and omacetaxine for myeloid hematological malignancies.
The genus Cephalotaxus comprises nine species, which are mostly concentrated in China, but are also found in eastern India, Thailand, the Korean peninsula and Japan. The anti-inflammatory and antiparasitic effects of Cephalotaxus fortunei Hook plants have been used in Chinese folk remedies for a long time and its antineoplastic effects have also been studied . Paudler et al.  isolated harringtonine and cephalotaxine from Cephalotaxus harringtonia in 1963 for the first time. In 1969, Powell et al. [3, 4] determined their structures and confirmed the antileukemic effects on mouse P-388 and L-1210 lines of some ester alkaloids isolated from Cephalotaxus harringtonia: harringtonine, isoharringtonine, deoxyharringtonine, and homoharringtonine (HHT). HHT differs from harringtonine in that it has a methylene group inserted in the side chain. Chinese scientists conducted research that confirmed the anti-leukemia effects of harringtonine and HHT in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In most of those studies, a racemic mixture of harringtonine and HHT was used. Despite similar chemical and preclinical activities, HHT was chosen over harringtonine because of its better extraction yield from its source, Cephalotaxus harringtonia[5–7]. A series of studies conducted in the United States confirmed the utility of this agent for CML [8, 9]. Since then, harringtonine and HHT have been widely used in the treatment of CML, AML and myelodysplastic syndrome (MDS), especially in China [10–13]. However, the clinical development of HHT in CML stopped with the discovery and popularization of the tyrosine kinase inhibitor (TKI), imatinib mesylate (Gleevec) . Recently, the interest in HHT for CML has been encouraged by positive results in patients who failed on imatinib therapy.
The natural purification of harringtonine and HHT has caused significant damage to the environment. In 1999, Robin et al.  reported, for the first time, the synthesis of semisynthetic HHT (sHHT). sHHT involves the direct esterification of cephalotaxine extracted from dry leaves of cephalotaxus, not from the bark. Only one 70th of the amount of cephalotaxus is required to extract sHHT compared with its natural counterpart, and it is also purer (99.7%). In addition, sHHT has excellent bioavailability by the subcutaneous (SC) route. sHHT is known currently as omacetaxine mepesuccinate (ceflatonin, CGX-653, Myelostat) and is being developed by ChemGenex Pharmaceuticals Ltd. (Menlo Park, CA, USA), in collaboration with Stragen Pharma (Geneva, Switzerland). Omacetaxine has recently been proved by FDA of the United States as an orphan drug to treat CML patients resistant to TKIs. In this paper, we will review the unique mechanism of action, and the development of HHT and omacetaxine for the treatment of hematological malignancies.
Mechanisms of action and preclinical studies
Harringtonine and HHT inhibit protein translation by preventing the initial elongation step of protein synthesis via an interaction with the ribosomal A-site [16, 17]. Recent crystallographic studies have shown that HHT blocks protein synthesis by competing with the amino acid side chains of incoming aminoacyl-tRNAs for binding to the A-site cleft in the peptidyl transferase center of the ribosome . HHT leads to a general decrease in synthesis efficiency of all proteins. An important short-term effect of HHT on cells is the rapid loss of proteins with short half-lives. A number of proteins related to cell survival and proliferation with short half-lives are encoded by mRNAs that possess complex 5′ UTRs that are G/C rich and have complex 3-dimensional structures (e.g. c-Myc, Mcl-1 and Cyclin D1). HHT and omacetaxine induce the rapid loss of a number of short-lived proteins from various cell lines of hematological malignancies. These short-lived proteins clearly regulate proliferation and cell survival and their loss is likely to be involved in the apoptosis induced by HHT and omacetaxine. An early event that triggers HHT- and omacetaxine-induced apoptosis is the downregulation of Mcl-1, which was originally identified as an antiapoptotic Bcl-2 family protein during differentiation of myeloid cells. These effects were replicated in primary cells obtained from patients with AML and patients with CML. Mcl-1 downregulation may result in an increase in free BH3-only proteins, such as Bim, tBid, Bik, and Puma, in addition to reducing the levels of beta-catenin and X-linked inhibitor of apoptosis (XIAP) proteins [19–24]. The short-lived protein c-Myc can promote expression of elongation initiation factor 4 F (eIF-4 F) proteins, which feed forward to promote translation of mRNAs that possess complex 5′ UTRs including c-Myc. As c-Myc is preferentially lost from cells treated with HHT, levels of mRNAs encoding eIF-4 F proteins are likely to be rapidly reduced and augment the effects of downregulation of protein translation initiation [25, 26].
In vitro studies showed that HHT could induce apoptosis of AML and MDS cells via upregulation of pro-apoptotic bax and downregulation of the protein inhibitor survivin [24, 27, 28]. Moreover, a study by Tong et al. showed that HHT might act as a broad-spectrum protein tyrosine kinase inhibitor that inhibits the phosphorylation of the signal proteins by oncogenic proteins such as JAK2V617F, Bcr-Abl, thus blocking the survival and proliferative signal pathway of primary AML cells and AML cell lines such as HEL, K562 and HL-60 cells .
Interestingly, HHT has proved synergistic with other agents active in CML, such as IFN-a, cytosine arabinoside (Ara-C), or both combined. The combination of all three agents was highly active against leukemic cells from patients with CML in the chronic phase (CML-CP) . Protein translation of mRNAs with complex 5′ UTRs in Bcr-Abl positive cells is upregulated via Bcr-Abl-mediated activation of phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways . The inhibition of Bcr-Abl by imatinib markedly reduced protein translation initiation. Imatinib interacts synergistically in inducing apoptosis of Bcr-Abl positive cells with compounds that interfere with translation directly or regulate protein translation initiation, which includes HHT and omacetaxine. HHT and omacetaxine also reduce Bcr-Abl protein levels in Bcr-Abl positive cells [34, 35]. Synergy was also observed when HHT and imatinib were used in combination against imatinib-resistant cell lines and against primary blastic cells obtained from patients with advanced phase CML (CML-AP) . HHT does not compete with ATP at the catalytic domain of the Bcr-abl kinase; therefore, it is conceivable that the activity of HHT against Bcr-Abl positive cells is independent of their Bcr-Abl mutational status. In fact, in vitro data have demonstrated that the activity of HHT against Bcr-Abl positive cells was similar irrespective of whether the cells harbored non-mutated Bcr-Abl or the imatinib-resistant E255K or T315I mutations . These studies raise the possibility that the efficacy of current CML therapy with TKIs may be increased by combined treatment with HHT and omacetaxine.
Leukemia initiating cells (LICs) are a population of stem cells that are capable of tumor initiation and maintenance of the disease. LICs in CML are thought to reside in a population of Bcr-Abl positive cells with characteristics of hematopoietic stem cells. Current TKIs do not kill these cells at a high frequency, but rather cause apoptosis in more differentiated Bcr-Abl positive cells of myeloid and lymphoid lineages . In recent years, many studies have shown that HHT and omacetaxine could effectively kill Bcr-Abl positive LICs in vitro and in a mouse model of CML. The reason why HHT and omacetaxine target Bcr-Abl positive LICs may be that Bcr-Abl positive LICs require expression of certain short-lived proteins (e.g. Mcl-1, β-Catenin and the β subunit of IL-3R). These proteins are preferentially lost to induce apoptosis and impair the renewal of Bcr-Abl positive LICs after treatment with HHT or omacetaxine [35, 38–41]. A recent study by Shen et al. showed HHT could effectively kill the LICs in the human AML cell line KG1 by inhibiting cell growth and inducing apoptosis, which was associated with activation of the caspase pathway and downregulation of anti-apoptotic protein Bcl-2 and phosphorylated-Akt .
HHT clinical development in CML
The initial clinical trials of cephalotaxine esters in patients with cancer were conducted in the 1970s [1, 5–7]. Nine of 15 patients with CML treated with HHT (5 mg d-1 ~ 7 mg d-1 for 7 ~ 10 days) achieved complete hematological remission (CHR) . In a subsequent study, 39% (32 of 82) of CML patients treated with HHT (intravenously, 4 mg d-1 to 8 mg d-1) achieved CHR . Huang et al. reported that 57.6% of 33 CML-CP patients treated with harringtonine (intravenously, 4 mg d-1, dose reduction and length of the course according the WBC counts) during 1991 ~ 1995 achieved CR . In a study carried out during 1996 ~ 2002, 76 newly-diagnosed CML-CP patients were treated with HHT (intravenously, 1.5 mg m-2 daily for 7 ~ 11 d every month). Among 55 patients with cytogenetic data, 38.2% achieved CyR (cytogenetic response) and 20% achieved MCR (major cytogenetic response), while only 2 of 10 patients with cytogenetic data achieved minor cytogenetic response in the group treated with hydroxyurea. The estimated 4-year overall survival (OS) was 46.2%, which was significantly higher than that of the group treated with hydroxyurea (27%, 10/27) . In 2008, Li et al. reported a low-dose and long term protocol of HHT (intravenously or intramuscularly, 1 mg d-1 for 8 weeks or 2 mg d-1 for 4 weeks, next cycle beginning after 4–5 weeks interval until 4 years), which resulted in a CHR of 66% (27 of 41) and with 5-year progression-free survival rate (PFS) 95% (39 of 41) .
The first two phase I studies performed in the United States was published in 1983 and 1984, in which, a highly purified form of HHT was administered daily for 1 to 10 days, with dose escalation from 0.2 mg m-2 to 8 mg m-2 daily. Cardiovascular collapse (hypotension and tachycardia) happened in approximately 25% of patients who received HHT at doses of 5 mg m-2 or 6 mg m-2 daily, which were occasionally fatal. The short infusion maximum tolerated dose (MTD) was <3 mg m-2 to 4 mg m-2 intravenously over 1 hour daily for 5 consecutive days [8, 46]. About 10 years later, a study performed by O’Brien et al. showed encouraging results. HHT was given as a single agent to 71 patients with late CML-CP at a dose of 2.5 mg m-2 daily for 14 days during the remission induction phase and for 7 days monthly during the maintenance phase. Seventy-two percent of 58 assessable patients achieved CHR and 31% of 71 patients achieved a CyR, including 15% MCyR and 7% complete cytogenetic response (CCyR). The major toxicities were myelosuppression which occurred in 39% of induction courses .
Subsequently, HHT was administered to 99 patients with early CML-CP using a dose schedule similar to that of the previous study of O’Brien et al., for six cycles, followed by the administration of IFN-a maintenance. The results showed that the rates of CHR, CyR and MCyR were 92%, 60% and 27%, respectively, which were superior to those in historic control patients after 6 months of IFN-a therapy . In another study performed by Kantarjian et al., the combination of HHT and low-dose ara-C was used to treat 100 patients in late CML-CP who had failed on IFN-a therapy. Seventy-two percent of patients achieved CHR, and 32% achieved CyR, including 15% MCyR and 5% CCyR . In a phase II study reported by Stone et al., the combination of HHT (2.5 mg m-2 daily) and ara-C (7.5 mg m-2 daily), given by continuous intravenous infusion for 7 days every 28 days, was administrated to 44 patients with newly-diagnosed CML-CP. The results showed an 82% CHR and a 17% MCyR . Moreover, O’Brien et al. treated 90 patients in early CML-CP with the triple combination of HHT, IFN-a, and low-dose ara-C, which yielded a 94% CHR and a 74% CyR, including 22% CCyR. After a median follow-up of 46 months, the estimated 5-year OS rate was 88%, and only 9% patients had progressed to CML-BP . In China, He et al. treated seven CML-CP patients with the combination HHT and AS2O3 (10 mg d-1 for 2 ~ 3 weeks, HHT 3 ~ 4 mg d-1 for 1 ~ 2 weeks). After the first course treatment, four patients achieved CHR . These studies suggest that HHT-based combination therapy results in improved clinical outcomes compared with single-agent HHT in patients with CML-CP.
The striking results obtained by TKIs impaired the development of HHT in CML. However, the distinct mechanisms of action and the remarkable effects of HHT on Bcr-Abl positive LICs and imatinib-resistant Bcr-Abl mutants (including T315I) in vitro, led to the return of HHT to CML therapy. Notably, the T315I Bcr-Abl mutation does not respond to any approved TKI in vitro or clinically, except ponatinib which was approved by US FDA more recently . The prognosis for chronic-phase CML patients with this mutation is poor. In a Phase I/II study, patients with CML who had achieved CyR but achieved a plateau in Bcr-Abl transcripts after treatment with imatinib for at least 2 years were given omacetaxine (1.25 mg m-2 twice daily for 1–3 days every 28 days). Of 10 evaluable patients, seven patients, including two with the Bcr-Abl mutation, had an appreciable decline in Bcr-Abl transcript levels. The results suggested the addition of omacetaxine should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease . In another Phase I/II study, six imatinib-resistant CML patients, including two patients with Bcr-Abl mutations, were treated with omacetaxine alone (2.5 mg m-2 intravenously over 24 hours, followed by 1.25 mg m-2, subcutaneously, twice a day, for 14 days in inducing period and for 7 days in maintenance period every month). CHR was obtained in all five evaluable patients and three had CyR, including one with CCyR. The Bcr-Abl mutations in both instances became undetectable . In 2007, Legros et al. reported that Bcr-Abl (T315I) transcript disappeared in an imatinib-resistant CML patient treated with omacetaxine for the first time . A study performed by Nicolini et al. investigated the effects of omacetaxine on non-mutated and T315I-mutated Bcr-Abl transcripts in eight TKI-resistant CML-CP patients. An initial rapid decline and a sustained disappearance of T315I-mutated transcripts were observed in 50% of the patients. As the non-mutated leukemic burden reduction was modest, two patients were submitted to nilotinib after 9 months of sustained Bcr-Abl T315I transcripts negativity on omacetaxine: the mutated transcripts remained undetectable after a median follow-up of 12 months on nilotinib challenge . In a recently reported phase II study, the efficacy of omacetaxine in CML-CP patients with T315I after TKI failure was assessed. Patients received omacetaxine 1.25 mg m-2 twice daily for 14 days every 28 days in induction period and for 7 days every 28 days in maintenance period. Seventy-seven percent of 62 patients achieved CHR, 23% achieved MCyR, including 16% with CCyR . These results suggested that HHT and omacetaxine might provide an effective treatment for CML patients with the T315I mutation. HHT and omacetaxine (a non-targeted therapy) might provide better disease control, allowing the disappearance of the mutated clone, probably elicited by the clone deselection after TKI release, and could allow for a safe TKI rechallenge in patients with resistant CML-CP. In consideration of the effect of HHT and omacetaxine on the LICs, the combination treatment of HHT or omacetaxine with IM in newly diagnosed CML may provide an approach to cure the disease and reduce the risk of relapse after the termination of IM treatment.
HHT clinical development in AML
The summary of studies of homoharringtonine-based regimens in the induction of acute myeloid leukemia
3-year OS, %
Huang 1989 
Low dose HHT + low Ara-c
Zheng 1989 
HHT + Ara-c
Bian 1993 
HHT + Ara-c
32 (5-year OS)
Fu 2001 
HHT + Ara-c
Yang 2005 
HHT + Ara-c
Xue 1995 
HHT + Ara-c + DNR
Xiao 2008 
HHT + Ara-c + DNR
Jin 2013 
HHT + Ara-c + DNR
Wan 1997 
HHT + Ara-c + aclarubicin
Song 2011 
HHT + Ara-c + aclarubicin
Jin 2013 
HHT + Ara-c + aclarubicin
Comparison of the toxicity of homoharringtonine and daunorubicin in the induction of acute myeloid leukemia
Subsequent studies also showed that an HHT based triple drug combination was highly effective in the treatment of AML. Xue et al. treated adult AML patients (newly diagnosed 38, relapse or refractory 12) with an HAD combination regimen (HHT 4 mg d-1, for 7 days, DNR 60 mg d-1 for 3 days, Ara-c 200 mg d-1 for 7 days). The result showed that the CR rate was as high as 86.0% (43/50), while the treatment related mortality (TRM) was only 4% . Xiao and colleagues showed that in 72 young untreated patients, this HAD regimen resulted in a CR rate of 86.1%, and a 3-year OS rate of 55.9% . In 1997, Wan reported an HAA regimen (HHT 3 mg d-1, for 3 days; Ara-c 200 mg d-1, for 7 days; aclarubicin 20 mg d-1, for 3 days) in the treatment of AML patients (20 newly diagnosed, five refractory or relapsed) and the CR rate was 76.0% . The efficacy of the HAA regimen in the treatment of young (14–60 years old) de novo AML patients was confirmed in studies performed by Jin and colleagues [65, 66]. The encouraging results led to an open-label, random, controlled, phase III study in 17 institutions in China . The results showed 73% of patients (150/206) with AML (non-acute promyelocytic leukemia (APL)) in the HAA (HHT 2 mg m-2 d-1 for 7 days, Ara-c 100 mg m-2 d-1 for 7 days, and aclarubicin 20 mg d-1 for 7 days) group achieved CR, which was significantly higher than that in the DA (DNR 40–45 mg m-2 d-1 for 3 days and Ara-c 100 mg m-2 d-1 for 7 days) group (61%, 125/205). Patients in CR were offered two cycles of intermediate-dose Ara-c (2 g m-2 every 12 h for 3 days). A 35.4% of 3-year event-free survival was observed in the HAA group versus 23.1% in the DA group. These results suggested an HHT-based triple drug combination, especially the HAA regimen, is a treatment option for young, newly diagnosed patients with AML (Table 1).
Comparison of the cardiotoxicitv of homoharringtonine and daunorubicin in adults with acute promyelocytic leukemia
Accumulative dose (mg.m-2)
Change of ST-T(n)
Nodal tachycardia (n)
Decrease of LVEF > 10% (n)
Increase of myocardial enzyme (n)
Liu 2012 []
The summary of studies of HAG regimen for AML, high-risk MDS and MDS/AML
Wei 2006 []
Refractory or relapsed AML
Zhang 2008 []
Refractory or relapsed AML
Ji 2010 []
Refractory or relapsed AML
Gu 2011 []
Refractory or relapsed AML
Liu 2006 []
Shu 2007 []
Su 2008 []
High-risk MDS or MDS/AML
Wu 2009 []
High-risk MDS or MDS/AML
Wu 2011 []
Elderly high-risk MDS or MDS/AML
The efficacy of priming HAG chemotherapy was also widely evaluated in elderly patients with AML. In a study performed by Liu et al., 31 elderly AML patients (aged 57–72) were treated with the HAG regimen (G-CSF 200 μg m-2, on days 1–14, HHT lmg m-2 on days 1–14, Ara-C 10 mg m-2, 1/12 h, on days 1–14), resulting in a CR rate of 58.1% and an OR rate of 80.6%, which were significantly higher than those (CR 32.4%; OR 55.9%) in the HA group (HHT 4 mg, on days 1–7, Ara-c 100 mg m-2, on days 1–7). The myelosuppression of the HAG regimen was milder than the HA regimen  (Table 4).
In the USA, a phase I trial conducted by Feldman et al. confirmed the HHT 4 mg m-2 for 7 days by continuous infusion in combination with Ara-c is safe and effective for patients with AML . However, there was no further related report after this trial in the USA and clinical data of omacetaxine in the treatment of AML is still absent. To fully estimate the effect and toxicity of HHT and omacetaxine compared with DNR in the treatment of AML, especially to compare HA regimen with standard DA regimen, multiple-centre, randomized, controlled phase III trials are required.
HHT clinical development in high-risk MDS or MDS evolving to AML (MDS/AML)
In China, harringtonine and HHT were also widely used to treat patients with high-risk MDS or MDS/AML. Cao et al. treated patients of MDS-RAEB or MDS/AML with low-dose harringtonine (0.5 ~ 1 mg, intravenously, daily or once every two days, for 10 ~ 15 days, with an interval of 5 ~ 10 days between the two cycles) during 1984–1989, CR was achieved in 4 of 13 patients . Subsequently, Ji et al. reported a 50% (7/14) CR rate in patients with MDS-RAEB or MDS/AML treated with low-dose harringtonine (0.5 ~ 1 mg d-1, intravenously, for 10 ~ 15 days, with an interval of 7 ~ 10 days between the two cycles) . In a phase II trial in the USA reported by Feldman et al., HHT was administered at a dose of 5 mg m-2 by 24-h continuous infusion daily for 9 days to patients with MDS or MDS/AML. CR was achieved in seven patients, and the OR rate was 28% (8/28). Significant myelosuppression was universal and resulted in a high incidence of induction deaths (13/28) caused by neutropenia-related infections .
The priming HAG regimen that was highly effective for refractory or relapsed AML was also widely used to treat high-risk MDS or MDS/AML (Table 4). In a study by Shu et al., 28 MDS-RAEB patients were treated with the HAG regimen, which resulted in a CR rate of 53.6% . Similarly, Su et al. reported that 46.67% of 33 newly diagnosed patients with high-risk MDS or MDS/AML treated with one course of HAG as induction chemotherapy achieved CR, while the CR rate in the group of HA regimen was 33.3%. The difference was statistically significant between the two groups . Meanwhile, Wu et al. reported a 46.9% CR rate in 32 patients with advanced MDS or MDS/AML after one course of HAG therapy . Wu et al. also evaluated the efficacy and toxicity of the HAG regimen as induction chemotherapy for elderly patients with high-risk MDS or MDS/AML. The CR rate was 57.6% (19/33). The median OS was 15 months. Grade 3/4 thrombocytopenia occurred in 28% patients and neutropenia in 34%. No treatment-related deaths occurred during the induction therapy. The data suggest that the HAG priming regimen is effective and safe as an induction therapy for patients, including elderly patients, with high-risk MDS and MDS/AML . These studies also suggested that stronger and alternative subsequent chemotherapy is necessary for patients achieved CR to maintain longer CR duration and better OS [84–87].
These data of HHT in the treatment high-risk MDS and MDS/AML were generally scattered and retrospective. So multiple-center prospective randomized trials are also needed to evaluate the effect and toxicity of HHT (or omacetaxine)-based regimens, especially HAG regimen in the treatment of high-risk MDS and MDS/AML.
HHT, a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action compared with other antitumor drugs. HHT inhibits protein synthesis by competing with the amino acid side chains of incoming aminoacyl-tRNAs for binding to the A-site cleft in the peptidyl transferase center of the ribosome. HHT induces the rapid loss of a number of short-lived proteins regulating proliferation and cell survival of various cell lines from hematological malignancies, which triggers HHT-induced apoptosis. In addition, sHHT (omacetaxine) caused less damage to the environment and another potential advantage is its excellent bioavailability by the SC route, which provides patients with the opportunity to self-administer their therapy. Preclinical studies have proved the synergistic effect of HHT with other agents, such as IFN-a, Ara-C and imatinib. Data from preclinical studies also showed the remarkable effects of HHT and omacetaxine on LICs and imatinib-resistant Bcr-Abl mutants (including T315I). Clinical studies suggested that HHT is effective for patients with CML-CP, and HHT-based combination can improve clinical outcomes. Clinical studies also suggested that HHT and omacetaxine may provide an effective treatment for TKIs-resistant CML patients with Bcr-Abl mutations, including T315I, and could allow a safe TKIs rechallenge. Many studies in China showed that HHT-based combination therapy is highly effective in the treatment of young, newly diagnosed AML, with at least comparable results with that of DA regimen. Clinical studies also showed that HHT-based regimens, especially the HAG priming regimen, are well tolerated and effective in patients with relapsed and refractory AML, high-risk MDS, MDS/AML or elderly patients with AML. The main adverse effects of HHT in the treatment of AML and MDS were myelosuppression and cardiotoxicity which were at least not more severe than DNR. But HHT was rarely used for the treatment of AML and MDS outside of China and there were also no clinical data of omacetaxine in the treatment of AML and MDS up to date.
Further studies should assess the suitability of combining HHT with TKIs and/or other agents in an attempt to improve current salvage regimens for patients with CML. In order to avoid Bcr-Abl mutating and cure the disease by killing LICs, clinical trials of the combination of HHT or HHT analogs with TKIs in the treatment of patients with newly diagnosed CML are also deserve to carry out. Studies should be performed to expand and validate the experiences of HHT in the treatment of AML and MDS in China with multiple-center prospective randomized trials.
The generation of HHT analogs with improved toxicity profiles and perhaps with oral bioavailabity should also be explored .
This work is supported in part by grants from the National Natural Science Foundation of China (No. 81090413, 81270638) to J.W. and (No. 30873042, 81100361) to S.L.
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