|Year : 2012 | Volume
| Issue : 1 | Page : 46-56
Optimizing second-line therapy for chronic myeloid leukemia
Department of Medical Oncology, Apollo Speciality Hospitals, Chennai, India
|Date of Web Publication||25-Jul-2012|
Department of Medical Oncology, Apollo Speciality Hospitals, Chennai
Source of Support: None, Conflict of Interest: None
Treatment of chronic myeloid leukemia has evolved from symptom control to long-term disease-free survival with cure potentially round the corner. This required faster, deeper, and longer response. Optimizing treatment decisions therefore requires clear understanding of and strict implementation of guidelines for shift from imatinib. In patients who are resistant to or intolerant of imatinib, second-line TKIs have to be selected carefully. Currently available data show comparable efficacy between nilotinib and dasatinib. With a better safety profile (especially with respect to grade 3 or 4 hematologic toxicity and clinically relevant non-hematologic toxicities), nilotinib becomes the preferred choice in most instances.
Keywords: Dasatinib, imatinib intolerance, mutation, nilotinib, resistance, toxicity
|How to cite this article:|
Raja T. Optimizing second-line therapy for chronic myeloid leukemia. Indian J Cancer 2012;49:46-56
| » Introduction|| |
Chronic myelogenous leukemia (CML) is a disorder of myeloid progenitor cells, characterized by excessive uncontrolled proliferation of the myeloid cells with shift to the left as a result of uninhibited tyrosine kinase activity due to the fusion bcr-abl gene that results from a balanced, reciprocal translocation generally between chromosome 22 and chromosome 9 called as Philadelphia chromosome. 
During the pre-imatinib era, treatment with oral drugs like busulfan and hydroxyurea allowed us to keep the white blood cell (WBC) count under control and relieve the patients of most of their symptoms.  Interferon (IFN) therapy permitted a small but important proportion of patients to even achieve complete cytogenetic response (CCyR).  The discovery of imatinib was a landmark breakthrough in medicine that enabled oncologists to block the proliferative effects of the chimeric bcr-abl gene with enough power to result in reducing the abnormal bcr-abl transcripts to undetectable levels in the majority of patients.  Being well established as standard of first-line care, data on the use of imatinib were rapidly generated in a large number of patients. This not only improved our understanding of the drug but also highlighted its limitations - since a fraction of the patients did not have the expected benefit from imatinib. 
Resistance to imatinib therapy
There are two types of resistance to imatinib therapy: primary resistance or intrinsic resistance is due to lack of efficacy from the onset of imatinib therapy, whereas secondary resistance or acquired resistance or relapse is due to loss of efficacy over time. 
Resistance can be identified at three levels - hematologic, cytogenetic, and molecular resistance. Hematologic resistance can be defined as lack or loss of normalization of peripheral blood WBC counts, differential leukocyte count, and spleen size. Hematologic response during advanced disease may also be qualitatively defined as failure to return to chronic phase (CP) disease status or occurrence of relapse.  Cytogenetic resistance can be categorized according to target level of cytogenetic response (CyR) at given therapeutic time points in terms of abnormal chromosomal karyotypes [major cytogenetic response (MCyR); less than or equal to 35% Ph-positive (Ph + ) metaphases at 6 months or CCyR at 12 months].  Molecular resistance refers to lack of complete molecular response (CMR). Quantitatively CMR can be defined as the absence of detectable bcr-abl transcripts by reverse-transcriptase polymerase chain reaction (RT-PCR).  And a major molecular response (MMR) is defined quantitatively as a bcr-abl/housekeeping gene ratio of less than 0.1% according to the international scale using individual conversion factors for individual labs. , Molecular relapse in patients with CCR refers to an increase in bcr-abl transcript level by fivefold to tenfold.  Once CMR is achieved (more than one negative result is obtained using nested PCR), relapse or loss of molecular response (MMR) is said to be documented if bcr-abl transcripts are detected in at least two consecutive samples.
Resistance to imatinib can occur during all three phases of CML. Clinical trials have suggested a relationship between the phase of disease, treatment order, and resistance.
Resistance in CP CML
A Phase II trial in 2002 by Kantarjian et al. involves CP CML patients in whom interferon-α (IFN-α) therapy had failed.  Of 454 enrolled patients, 5% failed to achieve a complete hematologic response (CHR) and 40% had less than M CyR after a median follow-up of 18 months, which suggested the possibility of primary resistance to imatinib. On 24-month follow-up, 4% failed to achieve CHR overall and 36% failed to achieve M CyR. The rate of secondary resistance or relapse was approximately 13%. The International Randomized Study of Interferon and STI571 (IRIS) researched imatinib efficacy in 553 patients newly diagnosed with CML-CP, who were treatment naive.  At 18 months, the rate of primary resistance to achieving CHR was approximately 5%, the estimated rate of failure to achieve an M CyR was 12%, and the estimated rate of relapse or progression was 10% after 24 months. Thirty-nine percent achieved a greater than or equal to a 3-log reduction in the level of bcr-abl transcripts after 12 months of imatinib therapy, as detected by quantitative RT-PCR. These are also the patients who achieved CCyR. Amongst these patients, the probability of progression-free survival (PFS) at 24 months was 100% versus 95% for patients with CCyR, but with less than 3-log reduction of bcr-abl levels.
At 60 months, the estimated rate of event-free survival was found to be 83% and an estimated 93% of patients were free of progression to accelerated phase (AP) or blast crisis (BC). Disease progression to AP or BC was found to occur in 35 patients (6%), loss of CHR or increase in WBCs in 14 patients (2.5%), loss of M CyR in 28 patients (5%), and 9 patients (2%) died during treatment for reasons not limited to CML. The estimated yearly rates for progression with a purview of all events noted above were 3.3%, 7.5%, 4.8%, 1.5%, and 0.9% in the first to fifth years, respectively, after the start of imatinib therapy. The yearly rates of disease progression to AP or BC were 1.5%, 2.8%, 1.6%, 0.9%, and 0.6% in the first to fifth years, respectively.  It was found that when taken together with the Phase II study results, the probability of refractoriness or relapse during imatinib therapy was lower among newly diagnosed CML patients treated with imatinib without prior therapy than among patients previously treated with IFN, and this trend was found to gradually decrease over time.  Among patients who achieve CyR, attainment of molecular responses is linked with lower rates of resistance and relapse. Early molecular responses correlate with prolonged CyRs, which are associated with long-term survival. ,
Resistance in advanced phase CML
The rates of primary and secondary resistance to imatinib were found to be increased with CML disease progression. In a Phase II study of 181 CML-advanced phase (AP) patients treated with imatinib, 66% failed to achieve CHR and 76% did not attain M CyR at 12 months.  In a Phase II trial with 229 myeloid CML-BC patients treated with either 400 mg or 600 mg imatinib daily, approximately 93% failed to achieve a CCyR and 84% failed to reach M CyR.  Thus, together from all these data, it can be inferred that the rates of resistance and relapse directly correlate with disease progression.
Mechanisms of resistance to lmatinib
Multitude of factors may contribute to imatinib resistance which include mutations within the kinase domain of bcr-abl, bcr-abl amplification or over expression, clonal evolution, and decreased imatinib bioavailability or cell exposure. ,,,, Of these, mutations and clonal evolution are clinically most relevant. 
bcr-abl mutations in resistant patients were reported in the frequency range from 42 to 90%, depending on the method used for their detection, the definition of resistance, and the phase of CML. , Patients in the AP and BC phases of the disease were found to have more mutations. However, in the CP patients, they were rarer and have been identified more frequently in patients with more than a twofold increase in bcr-abl transcript levels.  Also, it should be noted that Ph+ primitive cells have been reported to be less sensitive to imatinib in vitro and in vivo to harbor bcr-abl mutation even prior to imatinib exposure and to develop mutations rapidly under imatinib pressure. ,,,,
Various mutations have been found to have different biochemical and clinical properties. The T315I mutation and some mutations affecting the ATP phosphate-binding loop (the "P-loop") and the activation loop of bcr-abl confer a greater level of resistance, and unlike other mutations, cannot overcome imatinib resistance through dose escalation. Also, some other mutations, such as M351T, F359V, and L387M, are functionally of lower importance. ,, It is of prime importance that the detection of a kinase domain mutation must be interpreted within the clinical context.
Alternative pathways activation
Treatment with imatinib has been shown to activate phophatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in bcr-abl-positive cell lines and primary leukemia cells in vivo and in vitro. PI3K/Akt activation was found to be a critical mediator of cell survival in vitro during the early phase of imatinib resistance development before occurrence of robust bcr-abl mutation-dependent resistance to imatinib. By inhibition of imatinib-induced Akt activation in vitro using mTOR inhibitors and Akt-specific siRNA, the development of initial imatinib resistance can be effectively antagonized; however, in a clinical setting, this may increase the cost of therapy.  Additionally, acquired imatinib resistance may also be associated with over expression of Lyn and other Src tyrosine kinases. ,
The Src family kinases, Lyn and Hck, are activated in bcr-abl-expressing cell lines. Lyn kinase is over expressed and activated in an imatinib-resistant CML cell line that is generated by incubation of the parental line in increasing concentrations of imatinib and in samples from CML patients who were resistant to imatinib.  Suppression of this Lyn kinase by an Src kinase inhibitor resulted in reduced proliferation and survival of the imatinib-resistant, but not the sensitive cell line. 
Microarray analyses have shown that transcripts from genes with anti-apoptotic or malignant transformation properties and with involvement in signal transduction/transcriptional regulation are over expressed in CML cells that were innately resistant to imatinib. This seems to suggest that pathways downstream of bcr-abl and independent of its kinase activity may be important factors which may confer resistance to imatinib. 
CML disease progression is consistently associated with non-random, karyotypic abnormalities known as clonal evolution. It is a type of self-mutagenesis. 60-80% of CML patients who progress to more advanced stages of disease exhibit chromosomal abnormalities secondary to Ph chromosome. Clonal evolution has been demonstrated to occur during imatinib therapy and has been found to be associated with disease progression. ,,,,,,,,, A study by Mateusz Koptyra et al. in 2006 is evident of self-mutagenesis and successfully lists out all the factors involved in clonal evolution. 
Long arm deletion of the aberrant chromosome 9q+ (del9q+) was found to be associated with impaired prognosis after hydroxyurea and IFN therapy and was reported to be associated with attainment of lower rates of CHR, reduced CyR, and shorter PFS in late CP, AP, and BC patients treated with imatinib in one study; however, another study reports contradictory results. ,
Clonal evolution has also been associated with inactivation of p53. This tumor suppressor gene that resides on chromosome 17p is selectively activated by imatinib in bcr-abl-expressing cells as a result of bcr-abl kinase inhibition. Thus inactivation of p53 can lead to disease progression in CML and this may contribute to reduction of response to imatinib in vitro and in vivo, which is independent of bcr-abl kinase activity inhibition. Thus, p53 mutation and loss of p53 are associated with progression to imatinib resistance in CML. 
Chromosomal aberrations in Ph-negative cells
Some studies have indicated emergence of chromosomal abnormalities in Ph-negative (Ph−) cells in CML patients receiving imatinib. ,, However, the underlying mechanism for the appearance of these clones during imatinib treatment is still not completely understood (check). Imatinib may reveal the presence of pre-existing chromosomally abnormal cells. The emergence of cytogenetically unrelated Ph− clones with additional aberrations in CML may support the multistep model of leukemic transformation and the concept of genetic instability inherent in CML. An alternative hypothesis is that these cells could arise as a consequence of the hematopoietic proliferative pressures applied to normal cells under conditions where Ph+ cells are eradicated. As the same chromosomal abnormalities have emerged in Ph− cells in patients who were treated with agents other than imatinib and who had CyRs, it is unlikely that imatinib is responsible for the origination of these chromosomal abnormalities. Until now, most patients who developed chromosomal abnormalities in Ph− cells were not found to progress to advanced disease. More research needs to be done to determine whether proliferation of these abnormal Ph− clones contributes to relapse or the development of other clonal hematologic disorders, such as myelodysplastic syndromes, while on imatinib therapy.
Pharmacologic interaction, drug transport
Anti-cancer drug resistance often occurs through over expression of P-glycoprotein (Pgp), which is responsible for efflux of drugs and natural compounds out of the cell and is encoded by the multidrug resistance gene (MDR1). In a model of K562 cells with gradually increasing Pgp expression, on treatment with imatinib, intracellular imatinib levels declined in a Pgp-dependent manner. Now, decreased imatinib levels were associated with a retained phosphorylation pattern of the bcr-abltarget Crkl and failure to inhibit cellular proliferation and induce apoptosis. The use of a Pgp inhibitor such as cyclosporin A to modulate Pgp was shown to restore imatinib cytotoxicity in these cells.  Over expression of MDR1 is therefore considered to be an important clinical mechanism in governing the diversity of development of resistance to imatinib treatment, and Pgp expression has been observed more frequently in patients with advanced stage CML.
Active transport processes also mediate the influx and efflux of imatinib. Differential expression of influx, facilitated by transporters such as by the human organic cation transporter (hOCT1), and efflux, facilitated by MDR1, may be a critical determinant of intracellular drug levels and thus resistance to imatinib. 
Intolerance to lmatinib monotherapy
According to a study done by Cortes et al. in 2011, of the 321 patients in CML-CP and 137 patients in CML-AP enrolled in the Phase II nilotinib registration trial, 95 (30%) and 27 (20%), respectively, were intolerant to imatinib.  The median duration of previous imatinib therapy was 14 months for patients with CML-CP and 9 months for patients with CML-AP. Most patients [63 (66%) with CML-CP and 18 (67%) with CML-AP] previously received a maximum dose of <600 mg of imatinib per day. Only 5 (16%) and 2 (7%) imatinib-intolerant patients with CML-CP and CML-AP, respectively, were previously treated with at least 800 mg of imatinib per day, for a median duration of therapy at this dose of 3.1 months (range, 0.1-21.3 months) and 3.7 months (range, 0.3-7.1 months) for patients with CML-CP and CML-AP, respectively.
Of the patients who discontinued imatinib, a grade 3 or 4 adverse event (AE) was the reason for discontinuation in 72 (76%) and 21 (78%) of those with CML-CP and CML-AP, respectively. The remaining 22 (23%) patients with CML-CP (1 patient with unknown information assessed as intolerant by the investigator) and 6 (22%) with CML-AP were intolerant to imatinib because of persistent grade 2 AEs lasting at least a month. Sixty (63%) patients with CML-CP and 15 (56%) patients with CML-AP were intolerant to imatinib because of non-hematologic AEs such as edema, nausea, and vomiting, muscle cramps, musculoskeletal pain, diarrhea, and rash.
Thirty-one patients in CML-CP and nine patients in CML-AP (33% for both) were intolerant to imatinib because of hematologic AEs such as neutropenia and thrombocytopenia. Two (2%) patients with CML-CP included in this analysis exhibited other symptoms during imatinib therapy besides those that classified them as intolerant - one had conjunctivitis and the other had interstitial lung disease. Ten (11%) patients with CML-CP and 4 (15%) patients with CML-AP had unspecified reasons for imatinib intolerance, and 8 (8%) patients with CML-CP and 1 (4%) patient with CML-AP were intolerant to imatinib because of both hematologic and non-hematologic AEs.
Thus, because of resistance and intolerance to imatinib therapy in CML, it was obvious that search for new agents would begin; which ultimately gave rise to two new second-generation agents such as nilotinib and dasatinib. Now, let us look into the safety and efficacy parameters for these two agents as compared to standard dose imatinib and high-dose imatinib for second-line therapeutic agent in treatment for CML.
Thus, it is clear that optimization of treatment in patients with CML is possible only if intolerant or resistant patients are picked up early and switched to second-generation tyrosine kinase inhibitors (TKIs).
Clinicians must therefore be alert to identify patients who fail to achieve expected hematologic response, require increasing doses of imatinib, or lose their initial response. Patients who have chronic side effects like edema, muscle cramps, gastrointestinal (GI) toxicity, require doses of imatinib to be reduced or omitted, or those who require co-prescriptions to manage side effects are also suspect candidates, since tolerability will be the issue.
National cooperative cancer network (NCCN) recommends early switch from imatinib for such patients [Table 1]. 
Safety and efficacy of nilotinib over imatinib standard dose in second-line therapy for CML
In a post-hoc analysis of nilotinib registration trial by Kantarjian et al. in 2011, nilotinib therapy remained well tolerated after 24 months, and no changes were observed in the overall safety profile with longer follow-up.  Severe non-hematologic AEs were found to be infrequent, with grade 3/4 rash, headache, and diarrhea in 2% of patients, and all other grade 3/4 AEs in less than 1% of patients. Grade 3/4 AEs resulting in fluid retention or bleeding were found to occur in less than 1% patients and were uncommon. Most common biochemical abnormalities were grade 3/4 lipase elevation (18%), hypophosphatemia (17%), and hyperglycemia (12%); however, these were generally mild, transient, and easily managed. Grade 3/4 elevation of alanine aminotransferase and aspartate aminotransferase occurred in 4% and 3% of patients, respectively. Of all these patients, only two discontinued nilotinib therapy for elevated liver transaminases. Nilotinib-associated myelosuppression events were easily managed with dose interruptions or reductions or both. The change from baseline in mean time-averaged QTc interval calculated from the use of the Fridericia correction (QTcF) on day 8 at steady state was 5.1 msec. By the data cut-off, 8 patients (2.5%) had a >60 msec change from baseline in QTcF interval and 4 patients (1.2%) had a QTcF interval after baseline of >500 msec. No episodes of Torsade de pointes or death due to arrhythmias were noted.
In a post-hoc analysis of nilotinib registration trial by Kantarjian et al. in 2011, 24% of patients had additional chromosomal abnormalities and 42% had bcr-abl kinase domain mutation at baseline.  Overall, 59% of patients achieved MCyR. Of these, 56% were imatinib-resistant patients and 66% were imatinib -intolerant patients. Most patients who achieved MCyR also attained CCyR. Overall, 44% of patients achieved CCyR. CCyR was achieved in 41% of imatinib-resistant patients and 51% of imatinib-intolerant patients [Figure 1]. The proportion of patients who achieved MCyR (73% vs. 52%; P = 0.0002) and CCyR (58% vs. 36%; P = 0.0002) was found to be higher among patients who entered the study with a baseline CHR compared with patients who did not. CyRs were durable, with 77% of MCyR responders and 84% of CCyR responders maintaining their response at 24 months. Overall, 28% (82 of 294) of patients achieved MMR up to the cut-off. Among the patients who entered the study with baseline CHR, 38% achieved MMR versus 22% of patients without baseline CHR (P = 0.0036). An MMR occurred in 44% of patients who achieved MCyR and in 56% of patients who achieved CCyR.
|Figure 1: Survival of patients (n = 134) with major cytogenetic response (MCyR) on nilotinib as second-line therapy (after being diagnosed as having imatinib resistance or intolerance). Of the 134 patients who attained major cytogenetic response, 96% attained a stable response, 5 patients progressed to advanced disease and discontinued nilotinib treatment, whereas 16 patients lost their major cytogenetic response but were still continued on therapy,|
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Fifty-five percent (109 of 200) of the imatinib-resistant patients had bcr-abl mutation(s) at baseline and 14% (27 of 200) had mutations at baseline which, with the results of the present study, are known to be insensitive to nilotinib (E255K/V, Y253H, and F359C/V). Four imatinib-resistant patients had the T315I mutation at baseline. MCyR and CCyR were achieved by 68% and 50% of imatinib-resistant patients without mutations at baseline, respectively, versus 49% (P = 0.006) and 35% (P = 0.037) of patients with mutations at baseline.
Overall, the estimated PFS (progression to AP or BP or discontinuation due to progression or death) at 24 months was 64%. The estimated PFS at 24 months was higher for patients with baseline CHR (77%) compared with patients without CHR at study entry (56%). A total of 117 events have occurred: loss of CHR, 10; loss of MCyR, 38; and progression to AP or BP, 10. The estimated 24-month overall survival (OS) was 87%.
Safety and efficacy of nilotinib over imatinib high dose in second-line therapy for CML
Imatinib resistance is failure to achieve CHR within 3 months of therapy, any CyR within 6 months, or MCyR (Ph + less than equal to 35%) within 12 months, or the development of cytogenetic or hematologic relapse.
This study points out the efficacy of nilotinib in patients who are resistant to high-dose imatinib.  It is interesting to note that only 28% (77/280) of patients had previously received <600 mg of imatinib, 33% (91/280) had received between 600 and 800 mg of imatinib, whereas 44% (111/280) had actually received >800 mg of imatinib.
The results of this study indicate that the rates of MCyR with nilotinib were 48% (95%CI, 41.2%-55.7%) in patients with imatinib intolerance and 47% (95% CI, 35.7%-57.6%) in patients with imatinib resistance. CCyR was achieved in 88 patients (31%; 95%CI, 26.0%-37.2%). To add to this, five patients who entered the study with a complete CCyR maintained that response. Eleven patients (4%) documented MCyR during the study. The median time to MCyR during the study was found to be 2.8 months. Further, of the patients who achieved MCyR, 96% continued on nilotinib without progression or death for at least 6 months from the date of achieving their response [Figure 1].
The OS rate was found to be 95% at 12 months. As far as the safety of nilotinib is concerned, it is much more specific bcr-abl inhibitor, and hence is a better tolerable drug amongst the second-line therapy agents. 
Safety of nilotinib and dasatinib as second-line therapy for CML
In general, nilotinib was found to be a safer drug as compared to dasatinib. , [Table 2] shows the extent of myelosuppression with both the drugs. For instance, in CP CML, grade 3/4 neutropenia was seen in 31% of patients on nilotinib as compared to 36% patients on dasatinib. The difference was even more pronounced for patients in AP CML. Such differences were also documented for grade 3/4 anemia, it being 11% (CP CML) and 27% (AP CML) with nilotinib as compared to 13% and 47% with dasatinib, respectively. Thus, myelosuppression associated with nilotinib therapy is much less as compared to that associated with dasatinib therapy.
|Table 2: Comparison of hematologic toxicity in imatinib-intolerant or -resistant patients|
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Non-hematologic adverse drug reactions of significance were also higher with dasatinib as compared to nilotinib. Pleural effusions were seen in 18% (all grades; dasatinib dose 100 mg once daily) and 21% (grade 3/4; dasatinib dose 140 mg once daily). Severe hemorrhages, including fatalities, occurred in a significant number of patients on dasatinib (1% severe CNS hemorrhage, 4% severe GI hemorrhage, and 2% unspecified severe hemorrhage).
In the study of nilotinib by Kantarjain et al. in 2007, 318 patients were enrolled.  MCyR occurred in 48% and CCyR rate was 31%. Median time to MCyR was 2.8 months. Of those achieving MCyR, 96% remained on nilotinib without progression or death for at least 6 months. Of the patients who did not have a CHR at baseline (n = 185), 74% achieved CHR and the estimated 1-year survival was 95%.
The 24-month follow-up results represent a total of 321 patients. MCyR occurred in 59% and CCyR in 44%.  Of the responders, 77% (MCyR) and 84% (CCyR) maintained their response at 24 months. The estimated PFS and OS at 24 months were 64% and 87%, respectively.
In the dasatinib study by Kantarjian et al. in 2009, 150 patients received either dasatinib or high-dose imatinib.  For the dasatinib arm, the MCyR rate was 53%, the CHR rate was 93%, and the CCyR rate was 44% at a median follow-up of 26 months.
Rosti et al. published a good review in 2010, dissecting the safety and efficacy of nilotinib versus dasatinib, taking into account most of the variables. 
Meaning of imatinib resistance was uniform in most pivotal nilotinib and dasatinib studies. It was defined as absence of CHR by 3 months, lack of CyR by 6 months, no MCyR by 12 months, and a loss of CHR or MCyR at any time. However, in the dasatinib dose-optimization study, these criteria were not adhered to.  Patients who had less than CCyR at 12 months while on 400 mg/day of imatinib and were unable to tolerate dose escalation to 600 mg/day were also labeled as imatinib resistant. With such patients eligible for enrollment into the dose-optimization study, 20% patients actually had a baseline MCyR!
In addition, requirement for duration and dose of prior imatinib therapy was more stringent in the Nilotinib 2101 trial. Patients were labeled as imatinib resistant only if they had received dose-escalated imatinib therapy of 600 mg/day for at least 3 months prior to trial enrollment. In contrast, there were no imatinib dose-escalation requirements for enrollment in the dasatinib START-C trial or the dasatinib dose-optimization study. ,
The duration of prior imatinib exposure has been reported differently across the trials, making comparison difficult. For instance, in the Nilotinib 2101 trial, the median duration of prior imatinib use was 33 months for patients with CML-CP.  In the dasatinib START-C trial, the breakup was given in three time frames - less than 12 months, 12-36 months, and more than 36 months. Any attempt at comparing the results would therefore be: 53% of patients had prior imatinib therapy of greater than 36 months, 28% between 12 and 36 months, and 19% less than 12 months.  In the dasatinib dose-optimization study, 46% of patients had prior imatinib therapy of greater than 36 months, 33% between 12 and 36 months, and 22% less than 12 months. 
So, the argument of this review is though the overall criteria for START-C and Nilotinib 2101 studies appear to be balanced with regard to imatinib-resistant patients, it is difficult to compare the highest prior imatinib dose and duration between the trials. Further, the eligibility of patients with suboptimal responses to imatinib in the dasatinib dose-optimization study makes it very difficult to compare MCyR rates or other efficacy data with the Nilotinib 2101 study data.
Imatinib-intolerant patients: In the START-C trial, imatinib intolerance was defined as at least grade 3 non-hematologic toxicity or grade 4 hematologic toxicity that persisted for more than 7 days and which was related to imatinib at any dose.  However, it is important to note that in Nilotinib 2101 trial, intolerance was defined more stringently as: patients without an MCyR and who discontinued for persistent grade 3/4 AEs despite optimal supportive care, or grade 2 AEs related to imatinib despite optimal supportive care persisting for greater than or equal to 1 month, or recurring greater than 3 times with dose reduction or discontinuation. 
Thus, imatinib-intolerant patients currently in MCyR following imatinib therapy were not eligible for participation in the nilotinib study. Overall, 84% of intolerant patients enrolled into the study without MCyR. Of this 84%, 40% responded, from Partial Cytogenetic response (PCyR) to CCyR. These eligibility differences resulted in 44% of the imatinib-intolerant patients enrolled in the dasatinib START-C study having an MCyR at study entry and 20% of the patients (including some resistant patients) entering the dasatinib dose-optimization trial with pre-existing MCyR. ,,, To add to this, 51% of patients entered the dasatinib dose-optimization trial with a baseline CHR, whereas 36% of patients entered the Nilotinib 2101 trial with a baseline CHR. Research has shown that patients with a baseline CHR have a greater chance of achieving CyR. All patients were included in the efficacy analyses in the dasatinib studies. Thus, it is not possible to make a direct comparison with regard to efficacy.
Practical approach: How to select the right second-line TKI for your patient with CML-CP
In the absence of head-to-head comparison, there is still scope to arrive at the right choice for any patient. This will, of course, require attention to several crucial factors.
The efficacy of nilotinib was tested with strict application of the European LeukemiaNet guidelines. On the other hand, in the dasatinib dose-optimization trial, patients were eligible for entry even when they were in partial cytogenetic response. In addition, dose-escalation of imatinib required was also higher (>600 mg/day for at least 3 months) for introduction of nilotinib, whereas no such dose-escalation requirement existed for either of the dasatinib trials (START-C and dose optimization).
Was there any difference in the meaning of intolerance? In the dasatinib dose-optimization study, it was defined as grade 3 or worse toxicity that leads to imatinib discontinuation. On the other hand, in the Nilotinib 2101 trial, intolerance was more stringently defined (patients without any MCyR and who discontinued for persistent grade 3/4 AEs despite optimal supportive care or those persisting for more than 1 month or recurring more than 3 times in spite of dose reduction or discontinuation). In fact, any patient with MCyR was not eligible for entry into nilotinib study. As a result, 51% of patients entered dasatinib study with CHR compared to only 36% in the nilotinib study.
Now, let us look at the side effects. At all intervals after entry into the study, myelosuppression with dasatinib 70 mg bd was significantly higher than with nilotinib. In fact, neutropenia was higher even when dasatinib was given at 100 mg od. In the MD anderson cancer center (MDACC) study, the incidence of dasatinib-associated neutropenia was 21% as compared to 12% with nilotinib.
In addition, the nilotinib hematologic AEs tended to be predictable as well as reduced over time. Even when non-hematologic toxicities were compared, those on dasatinib increased with time from 6 to 24 months and no such increase was seen with nilotinib. Taking this into consideration along with the fact that pleural effusions and bleeding events are significantly higher with dasatinib, the picture gets clearer. Symptomatic pleural effusions with dasatinib have been reported as early as 1 week and as late as 2 years after initiation, with an incidence of 19% pleural effusion of grade 3 or 4, compared to less than 1% with nilotinib. This could be related to the Src kinase inhibition by dasatinib (which does not happen with nilotinib or imatinib). A similar differential mechanism may also be responsible for a fourfold higher incidence of bleeding events with dasatinib (inhibition of platelet function). Risk factors for bleeding while on dasatinib are thrombocytopenia and advanced phase of CML. Most episodes of bleeding occur 6 weeks after initiating dasatinib.
Initially, there was some fear of increased QT prolongation with nilotinib, which even led to a boxed warning. However, it is now clear that the QT prolongation is similar to that observed with dasatinib (<1%). AEs that are higher with nilotinib include elevation of pancreatic enzymes, transient increase in bilirubin, and hyperglycemia. So, the only patients who might be considered for dasatinib over nilotinib are those with past history of pancreatitis or poorly controlled diabetes mellitus. For the rest, nilotinib is certainly a safer option.
Implications of mutations and imatinib resistance
The incidence of baseline bcr-abl mutations in a study of 321 patients (mutation data from 281 of them) with CML in CP is shown in [Table 3]. 
|Table 3: Incidence of BCR-ABL mutations in imatinib-intolerant, imatinib resistant, and all patients|
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A higher proportion of patients with baseline mutations had disease progression compared with patients without mutations at baseline [46 (46%) of 100 patients vs. 23 (26%) of 87 patients]. Rates of progression also varied with the type of mutation.
[Table 4] shows the in vitro effect of imatinib, dasatinib, and nilotinib against various mutant bcr-abl cell lines. However, these drug concentrations do not correlate with clinical effectiveness in overcoming resistance when given in vivo. In one study, Redaelli et al. compared the computed in vitro value (ratio of Cmax/GI50 of imatinib to that of the drug) to the transformed in vivo response data.  They further correlated patient response in terms of CCyR and in vitro GI50 data by plotting previously published CCyR response rates for patients with specific mutations against the adjusted Cmax/GI50 values. These plots show that there is a poor correlation of clinical responses to both nilotinib and dasatinib against several of the mutations in vivo.  There were also some examples of mutations with similar in vivo exposure, yet significantly different rates of response exist. Overall, the activity of second-generation TKIs against all mutations was less than expected based on original in vitro GI50 or Cmax/GI50 calculations of systemic exposure. This transformed data suggests that among the three second-generation TKIs studied, nilotinib is the most potent in vivo, dasatinib is the second most potent, and bosutinib is the least potent inhibitor of most bcr-abl mutations. This in vitro mutation data is an indicator for predicting the in vivo response for predicting in vivo response and targeted drug concentration against various bcr-abl mutant forms.
|Table 4: Comparative efficacy profiles of imatinib, dasatinib, and nilotinib against selected BCR-ABL mutations|
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| » Conclusions|| |
Treatment of CML has come a long way in the last decade. The aim is shifted from symptom control to long-term disease-free survival and moving toward cure. Thus, it is important to pay careful attention to patient and disease status at regular intervals.
Our objective is faster, deeper, and more complete remission.  At the same time, it is crucial to watch out for early signs of resistance and intolerance so that therapy can be optimized as soon as necessary. ,,,, For a patient of CML requiring a shift from imatinib, it is the clinical judgment (based on the toxicity that needs to be avoided) that will ultimately decide which second-generation TKI shall optimize the outcome in individual patients.  Also, in most instances, nilotinib provides a better quality of life, fewer AEs, and comparable efficacy.
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[Table 1], [Table 2], [Table 3], [Table 4]
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