Treatment schedule with tyrosine kinase-inhibitors.
1. Introduction
Chronic myeloid leukemia is one of the most thoroughly studied and, undoubtedly, best understood neoplasms. There are about 4000 and 5000 new cases of CML every year in the USA. CML is a hematologic stem cell malignancy that typically evolves in 3 distinct clinical stages: chronic and accelerated phases and blast crisis. The chronic phase lasts several years and is characterized by accumulation of myeloid precursors and mature cells in bone marrow, peripheral blood, and extramedullary sites. The accelerated phase lasts 4 to 6 months and is characterized by an increase in disease burden and in the frequency of progenitor/precursor cells. The blast crisis lasts a few months and is the terminal phase of chronic myelogenous leukemia, characterized by the rapid expansion of a population of myeloid or lymphoid differentiation-arrested blast cells (Calabretta and Perrotti 2004; Radich 2007).
The cytogenetic hallmark of CML is the Philadelphia chromosome (Ph). It is a product of a reciprocal translocation between chromosomes 9 and 22 (t[9;22][q34;q11]). The
Treatment of this disease improved dramatically with the development of tyrosine kinase inhibitors (TKIs). Recently, the modern therapy of CML includes the use of TKIs (first and second generation), stem cell transplantation and clinical trials with novel agents such as novel multiple kinase inhibitors, Aurora kinase inhibitors, arsenic trioxide, hystone deacetilase inhibitors, proteasome inhibitors, other semi-synthetic drugs (Fig. 2). Imatinib is the golden standard in CML therapy and serves as first-line drug of choice in the chronic phase of CML (CP-CML) whereas second generation TKIs are taken in consideration after appearance of resistance to imatinib due to Bcr-Abl mutations. Accoridning to de Lavallade et al. only 62,7% of the patients treated with imatinibe achieved complete cytogenetic response (CCyR) and up to 5% of the patients present with advanced disease are poorly responsive to TKIs in general (de Lavallade, Apperley et al. 2008; Roychowdhury and Talpaz 2011). In other words, about one third of CML patients devepole intolerance or resistance to TKIs and therefore they need alternative therapies.
2. Tyrosine-kinase inhibitors
Imatinib, dasatinib and nilotinib are today the three clinically applied tyrosine kinase inhibitors of the fusion oncoprotein Bcr-BL for the treatment of CML and Ph (+) ALL (Fig. 3, Table 1). The constitutively active Bcr-Abl tyrosine kinase functions by transferring a phosphate group from ATP to tyrosine residues on various substrates (signaking molecules) to cause excess proliferation of myeloid cells typical for CML. Imatinib and the other two tyrosine kinase-inhibitors block the binding of ATP to Bcr-Abl, thus inhibiting its kinase activity (Fig. 4). They also act on other components of the cellular metabolism and signalling, e.g. Abl and ARG (Abl-related gene), C-kit receptor (KIT), receptors for platelet growth factor alpha (PDGFR-α) and beta (PDGFR-β), receptor for colony stimulating factor 1 (c-FMS) etc. (Kantarjian, Cortes et al. 2010). All tyrosine kinase inhibitors have good gastrointestinal absorption, which makes them suitable for oral application.
2.1. First generation tyrosine-kinase inhibitors — Imatinib
Imatinib was introduced for clinical use in 1998 for the treatment of CML. It showed high efficacy and revolutionized the disease management. Nowadays, Imatinib is the first-line drug of choice for the treatment of patients with CML in chronic phase and Ph (+) ALL as it induces long lasting remissions and is well tolerated as compared to conventional cytostatics (Fig. 2). Imatinib stops the progression of CML at early stages (Baccarani and Dreyling 2009).
Imatinib reaches Cmax within 2 to 4 h. Its total bioavailability is 98%. The half-lifes of Imatinib and its main metabolite, N-demethyl derivative (CGP74588), are 18 h and 40 h, respectively. Plasma protein binding (mainly albumin and α1-acid glycoprotein) for imatinib reaches 95%. The drug is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2, CYP2D6, CYP2C9 and CYP2C19. The main active metabolite of Imatinib is one N-demethylated piperazine derivative, formed by CYP3A4 and has
The superiority of Imatinib against IFNα was confirmed in the third phase of the International Randomized Study of Interferon and STI-571 (IRIS). A substantial cytogenetic response was achieved in 87% of the patients receiving Imatinib after 18 months, compared to 35% in those who received IFN. Complete cytogenetic remission was observed in 76.2% of the patients treated with Imatinib, compared to 14.5% of the treated with IFN. Molecular remission with reduction of the Bcr-Abl transcripts was found in 39% of the patients treated with Imatinib, against 2% for IFN. 325 (71%) of 456 patients who had achieved complete cytogenetic remission with Imatinib sustained their remission on the sixth year of treatment. Tracking patients over the 6-year exploration period indicated that Imatinib had a favourable and long-lasting safety profile, as there were no new adverse events during the 5th and 6th year of study. The use of Imatinib as first-line drug for CML did not affect subsequent treatment of patients with allogeneic hematopoietic stem cells transplantation (Kantarjian, O'Brien et al. 2003; Deininger 2008; Baccarani and Dreyling 2009).
2.2. Second generation tyrosine-kinase inhibitors
2.2.1. Nilotinib
Nilotinib is a highly selective ABL inhibitor and derivative of Imatinib and can overcome some mutations that can cause imatinib resistance with the exception of T315I. During first phase clinical trial, Nilotinib was tested at doses of 50 mg once daily to 600 mg twice daily in 119 Imatinib-resistant CML patients at various stages of the disease. 92% of the patients in chronic phase achieved complete hematologic remission. 72% of the patients in the acute phase of CML presented hematologic remission and 48% of them had a cytogenetic response. 39% of patients with CML in blast crisis demonstrated a hematologic response and 9 of them (27%) had a cytogenetic response. The results of the study defined a recommended dose of 400 mg twice daily (Table 1). Nilotinib adverse reactions include small pleural or pericardial effusions. The most common adverse effects during the study were thrombocytopenia (20% -33%), neutropenia (13% -31%), elevated bilirubin (7%), and increased serum lipase (5% -15%). Grapefruit and other food that inhibits hepatic metabolism (mainly CYP3A4 inhibitors) should be avoided. Nilotinib is not recommended for patients with prolonged QT-segment, and drugs that prolong the QT-segment should not be given during treatment with Nilotinib (Kantarjian, Giles et al. 2007; Olivieri and Manzione 2007; Weisberg, Catley et al. 2007; Melo and Chuah 2008; Giles, Rosti et al. 2010; Kantarjian, Cortes et al. 2010; Kantarjian, Giles et al. 2010; Quintas-Cardama, Kim et al. 2010).
2.2.2. Dasatinib
Dasatinib is another ABL kinase inhibitor that binds to the active conformation of the ABL-kinase domain and to the structurally related kinases of the Src-family.
Nowadays, the choice between treatment with dasatinib and nilotinib in imatinib resistant patients is made on the basis of the history of comorbidities, since no such very important comparative study of both drugs has been made so far. Therefore, patients with a history of lung disease may be more suitable for treatment with nilotinib, while patients with pancreatic disease could benefit from treatment with dasatinib. Patients bearing the T315I mutation are resistant to treatment with both dasatinib and nilotinib. Such patients should be offered the option for inclusion in clinical trials or allogeneic bone marrow transplantation (Kantarjian, Cortes et al. 2010).
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Imatinib | 400 mg | p.o. | Daily |
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Dasatinib | 70 mg 100 mg |
b.i.d.p.o. р.о. |
Daily |
Nilotinib | 400 mg | b.i.d.p.o. | Daily |
Imatinib (high-dose) | 400 mg | b.i.d.p.o. | Daily |
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Imatinib | 400-600 mg | p.o. | Daily |
Dasatinib | 70 mg | b.i.d.p.o. | Daily |
Nilotinib | 400 mg | b.i.d.p.o. | Daily |
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Imatinib | 260 mg/m2/d 340 mg/m2/d |
p.o p.o.. |
daily daily |
2.3. Resistance towards TKI — Mechanisms and management
The most important problem in the target therapy of CML today is the development of resistance towards TKIs. Lucas et al. reported after a population-based study in Northern England that about 50% of the patients treated with imatinib developed intolerance or failure up to two years after initiation (Lucas, Wang et al. 2008). Responses obtained in patients with advanced desease were also not durable. CCyR at 6 years after initiating imatinib therapy is determined by 57% patients and 55% remain on the treatment after 8 years (Burke, Swords et al. 2011). Even nilotinib at best achieved CCyR in 80% of the treated patients (Rosti, Palandri et al. 2009). In summary, there is a significant minority of patients developing resistance towards imatinib and second generation TKIs. Investigators distinguish between primary and secondary resistance. Secondary treament failure or desease replase is characterized by the loss of already achieved complete cytogenetic or hematological response and is dependent on different factors such as age, stage of disease, duration of INF therapy and duration of response to initial therapy. In contrast, primary resistance is the failure to achieve CCyR or hematologic response and is not very well investigated and understood. Concernig leukemic cell proliferation and survival two other models of imatinib resintance could be outlined: on one hand leukemic cells became independent from the fusion oncoprotein for their survuval and proliferation and, on the other hand the tyrosine kinase Bcr-Abl circuvented the inhibition by imatinib or other TKIs, e.g. appearance of the mutation T315I (Burke, Swords et al. 2011; Roychowdhury and Talpaz 2011).
The mechanisms of imatinib resistance could be classified as either Bcr-Abl dependent or Bcr-Abl independent. Bcr-Abl dependent mechnisms include Bcr-Abl amplification, kinase domain mutations and Bcr-Abl induced genomic instability. Bcr-Abl independent mechanisms are usually related to drug complience and metabolism, drug transport, clonal evolution, escape of the primitive progenitors from therapy and activation of alternative signal transduction pathways.
Kinase domain mutations belong to the most important mechanisms of resistance towards TKIs. They were identified in clinical studies with patients with imatinib resistance (initial or developed during the therapy) where 30% of the patients had primary resistance and 57% - secondary resistance (Shah, Nicoll et al. 2002; Soverini, Martinelli et al. 2005). Today over a 90 mutations in the Bcr-Abl fusion gene are described and they affect 57% of the amino-acid residues. Some of these mutations cause a direct steric interference to drug-enzyme binding or alter allosterically the kinase domain activity and are reported to be the main reason for treatment failure in many clinical trials. Mutations in the P-loop are assigned as poor prognistic factor. In particular, the T315I mutation accounts for the majority of secondary resistance (Burke, Swords et al. 2011). The T315I mutation is a single amino-acid substitution of isoleucine with threonine at position 315 on c-Abl. It alters the ATP-binding site of the tyrosine kinase, confers cross-resistance to nearly all clinically applied TKIs and correlates with decreased cytogenetic response and progression free survival rates. In summary, in clinical studies about 50% incidence of this mutation had been reported for patients with secondary resistance. Therefore, introduction of new drugs is substantially needed (Bradeen, Eide et al. 2006). However, there are studies reporting that kinase domain mutations were found also in patients with CCyR and in remission, but only few of them eventually developed disease relapse. It is evident that not all kinds of resistance are due to Abl-mutations and not all mutaions could lead to resistance (Branford, Melo et al. 2009; Roychowdhury and Talpaz 2011). Correlations based on
Pharmacokinetic characteristics of the TKIs were also demonstrated to be important for better clinical outcomes. Imatinib is substrate for the liver enzyme CYP3A4 which converts it into active metabolite. A higher enzyme acitivity correlated with higher rate of complete molecular responses (Green, Skoglund et al. 2010). The α-1-acid glycoprotein directly binds imatinib, thus increasing its clearance. Therefore, patients with high levels of this protein demonstrated lower plasma concentrations of imatinib which worsened the therapeutic response (Delbaldo, Chatelut et al. 2006). Through
Another reason for developing resistance towards targeted CML therapy is provided by the stem cell hypothesis. According to some investigators there is a reservoir of primitive progenitors that are capable of self-renewal or progression
The strategies to overcome resistance include first optimization of the front line therapy with imatinib such as escalation of the daily dose up to 800 mg and second the introduction of second generation TKIs such as dasatinib, nilotinib (Table 1) and other new compounds that are still in clinical trials (Jabbour, Kantarjian et al. 2009; Roychowdhury and Talpaz 2011). Dasatinib and nilotinib were successfully used in patients in accelerated phase or blast crisis after Bcr-Abl mutation analysis that demonstrated other mutations than T315I. Ponatinib, a new multiple kinase inhibitor, showed high activity against T315I mutants
After failure of imatinib and a second generation TKI, most patients could be included in ongoing clinical trials. Next, some of the novel agents beeing evaluated in Ph(+) leukemias are listed.
3. Experimental drugs for CML therapy
3.1. Tyrosine kinase inhibitors
3.1.1. Bosutinib
Bosutinib was developed to overcome the resistance to first and second generation TKIs and is still in clinical trials. It was shown to possess a high antiproliferative activity
3.1.2. Other experimental tyrosine kinase inhibitors
There are also new types of compounds inhibiting pathobiochemical pathways, resulting from the
Other new TKIs are the SFK/Abl kinase inhibitor, the anilino-quinazoline AZD0530; the purine derivates AP23464 and its analogue AP23848; the pyrido-pyrimidines, PDI66326, PDI73955 and PDI180970; thje pyrazolo-pyrimidines, PP1 and PP2; the acetylanes AC22 and K1P. These compounds have not been developed for clinical use yet (Melo and Chuah 2008; Bixby and Talpaz 2009; Burke, Swords et al. 2011).
3.2. Aurora kinase inhibitors
The Aurora kinase familiy consists of serine-threonine kinases that are crucial for different stages of the mitosis. There are two family members Aurira A and B and are overexpressed in some neoplasias. Following Aurora kinase inhibitors are in pre-clinical and clinical evaluation: PHA-739358 (danusertib), AT9283, MLN8237XL-228, KW-2449 and MK-0457. Danusetib showed safety profile and efficacy in patients bearing the T315I mutation in phase I clinical study. AT9238 is a multi-kinase inhibitor which also inhibited cells with the T315I mutation. It was well-tolerated during phase I clinical trial and shwed promising anti-leukemic activity (Cortes-Franco, Dombret et al. 2009; Howard, Berdini et al. 2009; Moore, Blagg et al. 2010; Tanaka, Squires et al. 2010; Burke, Swords et al. 2011).
3.3. Heat shock protein 90 inhibitor
As a molecular chaperone that interacts with various proteins (Raf, Akt, FLT-3 and Bcr-Abl) Hsp90 maintains those proteins in a stable and functional conformation. Geldanamycin and its derivative, 17-allylamino-17-demethoxygeldanamycin (17-AAG) bind to the ATP-binding pocket of Hsp90 and inhibit its chaperone activity. This leads to downregulation of Bcr-Abl and also induction of apoptosis in CML cell lines. Gledanamycin and 17-AAG inhibited the cell growth of some mutant lines (E255K and T315I). Hsp90 has its limits and there are some cross-resistant types. Combination therapy with imatinib and 17-AAG led to synergistic inhibition of growth and induction of apoptosis in cross-resistant cell lines but not in the imatinib-sensitive counterparts. 17-AAG may also block the imatinib efflux (Melo and Chuah 2008; Burke, Swords et al. 2011).
3.4. Arsenic trioxide
Another compound that induces apoptosis in Bcr-Abl-positive cell lines and reduces proliferation of CML blasts without affecting the CD34+ progenitors, is the arsenic trioxide (As2O3). The combination of As2O3 with imatinib exerted additive to synergistic effect. This combination induced cell death in imatinib-resistant cell lines with overexpressed Bcr-Abl or bearing M351T or Y253F mutations, but it does not affect the T315I mutants (Melo and Chuah 2008; Roychowdhury and Talpaz 2011).
3.5. Homoharringtonine
Homoharringtonine (HHT), a by-product of a plant alkaloid, inhibits protein synthesis and induces apoptosis. The combination of HHT with imatinib is synergistic or additive on CML derived cell lines. Omacetaxine and chemgenex are semisynthetic HHT derivatives that combined with imatinib showed promising activities. Omacetaxine is now in phase II trials with TKIs-resistant patients with or without the T315I mutation (Melo and Chuah 2008; Burke, Swords et al. 2011).
3.6. Histone deacetylase inhibitors
Histone deacetylases (HDAC) are the catalysts in deacetylation of lysine residues at the amino termini of core nucleosomal histones. Histone deacetylase inhibitors (HDI) such as suberoylanilide hydroxamic acid (SAHA, vorinostat), generate hyperacetylated histones, causing transcriptional upregulation of the cyclin-dependent kinase inhibitor, p21, cell-cycle arrest and apoptosis in tumor cells. SAHA also induces expression of a key cell-cycle regulator p27, and its application is associated with downregulation of the p210 Bcr-Abl protein. There is a synergetic interaction between SAHA and imatinib on CML cell lines. The mentioned combination induces apoptosis in imatinib-resistant CML cell lines as well. The co-treatment with nilotinib and the HDI LBH589 (panobinostat) was very effective in inducing apoptosis in K-562 and LAMA-84 CML cell lines. LBH589 showed efficacy in imatinib-resistant cell lines bearing the T315I and E255K mutations and this was associated with depletion of Bcr-Abl. A published study showed that when combined with imatinib, the HDI valproate can increase the antileukemic efficacy and sensitize imatinib-resistant CML cells (Kantarjian, O'Brien et al. 2003; Melo and Chuah 2008; Burke, Swords et al. 2011).
3.7. Proteasome inhibitors
Proteasomes are responsible for the degradation of different cellular proteins. The proteasome inhibitor bortezomib was shown to inhibit proliferation, to stop the cell cycle in the G2/M phase and to promote apoptosis in imatinib-sensitive and imatinib-resistant CML cell lines. Co-treatment with bortezomib and imatinib isn’t recommended because there are some antagonistic interactions. However, if a low dose bortezomib exposure of CML cell lines is followed by imatinib, there are some additive effects. Synergistic interactions between bortezomib and the HDI SAHA are reported, and between bortezomib and flavopiridol in
3.8. Semi-synthetic drugs
Semi-synthetic drugs flavone and flavopiridol are going through clinical trials. They target multiple cyclin-dependent kinases. Flavopiridol showed a very promising activity in combination with imatinib for inducing apoptosis in Bcr-Abl-positive CML cell lines (Melo and Chuah 2008).
3.9. Farnesyl Transferase Inhibitors (FTIs)
Current FTIs under investigation and with a potential as antileukemic agents are tipifarnib and lonafarnib. They are inhibitors of the Ras-MAPK signal pathway which was shown to couple to Bcr.Abl through protein-protein interactions and to play a central role in leukemogenic transformation. Tipifarnib is in Phase II trial involving 22 patients with CML. Complete or partial hematological response was achieved in 32% of the patients. The combination imatinib and tipifarnib was well tolerated and active in patients with imatinib-resistnat CML – a partial cytogenetic response was achieved in patients harboring the T315I mutant. Lonafarnib is a selective inhibitor of primary progenitor cells derived from CML patients. It reduced colony formation of progenitor cells and showed activity in imatinib-resitant CML cell lines. However, the reports from a pilot study demonstrated that only 2 of 13 patients achieved a clinical response.
3.10. Raf-1 inhibitors
Sorafenib (BAY 43-9006) is a multi kinase inhibitor of the RAS/Raf pathway which is involved in leukemogenesis downstream from Bcr-Abl. Drug concetrations of 5-10 µM were found to induce apoptosis via the mitochondrial pathway in imatinib-rsistant cell lines. The combination between sorafenib and vorinostat (HDAC inhibitor) triggers cell dysfunction through Mcl-1 downregulation and p21 inhibition. Sorafenib is approved for the treatment of hepatocellular and renal cancers and Phase I and Phase II trials are carried out in CML patients (Burke, Swords et al. 2011).
3.11. MEK inhibitors
CI-1040 was the first MEK inhibitor which entered a clinical trial in CML patients. It has been studied in combinations with imatinib, dasatinib, HDAC inhibitors, arsenic trioxide and HSP 90 inhibitors. The last two combinations were tested with a positive effect in patients with T315I mutation. Because of the challenging pharamokinetic properties, clinical advancement is unlikely, but a derivate (PD0325901) is under development (Burke, Swords et al. 2011).
3.12. mTOR inhibitors
The protein kinase, mTOR (mammalian target of rapamycin), is a downstream mediator in the PI3K/Akt pathway which controls cell growth and survival. Rapamycin (sirolimus) is the prototype compound of this group, but it has poor aqueous solubility and chemical stability, limiting its clinical usefulness. However, in a small clinical trial four out of six patients with imatinib-resistant disease responded to oral rapamycin. Rapamycin also significantly inhibited the cell growth in Ph+ cell lines with or without the T315I mutation. The combination between imatinib and another mTOR inhibitor, everolimus, was associated with an increased expression of c-Abl and inhibition of Bcr-Abl. In the presence of inhibited Bcr-Abl, c-Abl enetrs the nucleus an modulates apoptosis. A Phase I trial with imatinib and everolimus has been completed while a study with temsirolimus is currently in accrual (Burke, Swords et al. 2011).
4. Interferons
Before the era of TKIs and since the 1980s interferon-α had constituted the first-line therapy for CML patients in the chronic phase of the disease. Interferon induced long-lasting remissions in up to 80% of the patients with complete cytogenetic response. After interferon therapy they had disease-free survival beyond 10 years. There are some clinical trials that showed succesful combinations between TKIs and interferon which provided an adjunct immunologic response during induction or maintenance therapies. Treatment with interferon after imatinib was shown to be followed by a possible remission status (Burchert, Muller et al. 2010; Roychowdhury and Talpaz 2011). Howerver, additional data are required in order to clarify the role of interferon in conjunction to the TKI therapy.
5. Stem cell transplantation
Allogeneic stem cell transplantation (ASCT) was first line therapy for CML patients for many years. In the imatinib era, however, ASCT is becomning second or even third option for these patients if hematological, cytogenetic or molecular remission with imatinib is not achieved after 3,12 and 18 months, respectively (Baccarani and Dreyling 2009). ASCT is still the only treatment that offers a definitive cure. The risks of ASCT are some mortality rate, graft-versus-host disease (GVHD), potentially lethal acute or chronic infections death and risk of second malignancy. There are no data about negative influence on ASCT of pre-treatment with tyrosine-kinase inhibitors. In a single institution in the USA between 1995 and 2000 131 CP CML patients underwent allogeneic SCT with bone marrow or perpheral blood from related donors. In the 3 year long period, the probability of disease-free survival was 78%. The survival and disease recurrence rates were estimated at 86% and 8% respectively. The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) published own data. In the period between 2000 and 2003 3018 patients were treated with ASCT for CML. The 2-year survival rate was 61%, the transplant-related mortality rate was 30%, and the rate of disease recurrence was 22%. Better results were observed in patients who underwent ASCT at the time of first CP using as a donor an HLA-identical sibling. The 2-year survival rate in this case was 74%, transplant-related mortality rate 22% and disease recurrence rate 18%. This confirms the fact that the outcome of ASCT is highly dependent on risk factors. EBMT study showed that favorable factors are sibling donor, treatment at early stage of the disease, under 12 months after diagnosis, and younger age of the patient (age under 20 years is better than 20-40 years, and above 40 the risks are higher). If successful, ASCT can lead to long-lasting results. In a 10-year study of patients transplantated with an allogeneic bone marrow from siblings, the mean time of hematologic or cytogenetic disease recurrence was 7.7 years and 46% of the long-term survivors never developed disease recurrence.
One of the main problems standing in front of ASCT is that most of the patients don’t have a suitable HLA-matched sibling. National Marrow Donor Program institutions in the U.S. conducted a study in the period between 1988 and 1999 that compared results from 2464 unrelated donor bone marrow transplantations with 450 HLA-identical sibling donor transplantations. The results from this study confirm that patients transplantated with bone marrow from a non-relative donor have greater risk of complications. However it is important to mention that data from this study didn’t show a significant difference in the 5-year survival rate between the two types of donors if the transplantion was made within 1 year after diagnosis (Jabbour, Cortes et al. 2007).
6. Conclusion
Imatinib is now the most common first line drug for the treatment of CML and is a hallmark of target drug therapies for malignant diseases. However resistance to this drug is a major problem that can’t be overcome by increasing the dosage (Jabbour, Kantarjian et al. 2007; O'Hare, Eide et al. 2007). Single agent therapy with imatinib may not be the best long-term option in many of the CML patients and other approaches should be considered. There are many novel compounds that are in development and in preclincal and clinical trials, some of them showed very promising results. Dasatinib, nilotinib and bosutinib are representatives of the newer generation TKIs which are effective and safe to use in imatinib-resistant and/or -intolerant CML patients. It is very likely that new Bcr-Abl mutants will become resistant to these small-molecule inhibitors. Therefore, other therapeutic approaches are required. The combination of TKIs with other inhibitors of non-Bcr-Abl targets is needed to overcome the resistance.
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