Search

Background: A limited amount of data has been published in chronic-phase chronic myeloid leukemia (CP-CML) patients aged >75 years treated frontline with second-generation tyrosine kinase inhibitors., Aims: To address this issue in a clinical 'real-life' setting, we retrospectively analyzed 45 CP-CML patients (pts) followed in 20 Italian Centers and treated frontline with dasatinib (DAS)., Patients and Methods: Median age was 78.4 years (range 75-89.2 years). DAS starting dose was 100 mg QD in 35 pts (77.7%), 80 mg QD in 1 pts (2.2%) and 50 mg QD in 9 pts (20.1%), respectively. The median follow-up was 42.6 months (IQR 20.4 - 63.3)., Results: Grade 3 and 4 side effects, both hematological and non-hematological, were detected in 6 (13.3%) and 12 (26.6%) pts, respectively. Pleural effusions of all grades occurred in 13 pts (28.8%) after a median period of DAS exposure of 14.7 months (IQR 3.0 - 33.1). The rates of DAS dose reduction and permanent drug discontinuation were 53.3% and 20.0%, respectively. As the best response, 42/45 patients (93.3%) achieved a complete cytogenetic response (CCyR), 35/45 (77.7%) a major molecular response (MMR) and 24/45 (53.3%) a deep molecular response (both MR 4.0 and MR 4.5). Only 1 patient (2.2%) progressed to the blast phase after 13 months of therapy; 8 deaths were observed (1 CML-related and 7 CML-unrelated). Cumulative event-free survival and overall survival at 36 months were 64.7% (95%, CI 49.4 - 80.0) and 82.3% (95%, CI 70.3-94.3), respectively., Conclusion: These findings, although evaluated in a limited and selected cohort of patients, suggest that DAS might be effective in older patients (aged >75 years) affected by CP-CML with acceptable toxicity.

It is judged safe to discontinue treatment with tyrosine kinase inhibitors (TKI) for chronic myeloid leukemia (CML) in experimental trials on treatment-free remission (TFR). We collected a total of 293 Italian patients with chronic phase CML who discontinued TKI in deep molecular response. Seventy-two percent of patients were on treatment with imatinib, and 28% with second generation TKI at the time of discontinuation. Median duration of treatment with the last TKI was 77 months [Interquartile Range (IQR) 54;111], median duration of deep molecular response was 46 months (IQR 31;74). Duration of treatment with TKI and duration of deep molecular response were shorter with second generation TKI than with imatinib ( P <0.001). Eighty-eight percent of patients discontinued as per clinical practice, and reasons for stopping treatment were: toxicity (20%), pregnancy (6%), and shared decision between treating physician and patient (62%). After a median follow up of 34 months (range, 12-161) overall estimated TFR was 62% (95%CI: 56;68). At 12 months, TFR was 68% (95%CI: 62;74) for imatinib, 73% (95%CI: 64;83) for second generation TKI. Overall median time to restart treatment was six months (IQR 4;11). No progressions occurred. Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and second generation TKI is feasible and safe in clinical practice., (Copyright© 2019 Ferrata Storti Foundation.)

Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a "real-life" cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: As survival of patients with chronic myeloid leukemia (CML) is dramatically improved over time, the prevalence of the disease is steadily increasing. At this moment, five different tyrosine kinase inhibitors (TKIs) (imatinib, nilotinib, dasatinib, bosutinib and ponatinib) are approved for the treatment of CML. Medical and patients needs nowadays are attention to quality of life (QoL) and drug side effects; overcoming suboptimal responses; preventing progression and possibly discontinuing the drugs. Monitoring is essential to improve on treatment and on the possibility of cure, because it allows patient adapted therapies, according to patients morbidities and early responses., Areas Covered: This review focuses on clinical results of imatinib and second- and third-generation TKIs that have been tested in the setting of second-line and front-line treatments. The most promising new drugs in course of clinical investigations are also reported., Expert Opinion: The scientific community is focusing on the optimization of the use of the drugs already available, to be also used in association with other experimental drugs directed to several signaling transduction pathways of BCR-ABL, in order to improve the efficacy on resistant cases, and on leukemic stem cells, keeping in mind the issues of long-term safety, QoL and the need for treatment - free remission.

In chronic myeloid leukemia (CML), the presence of a specific chromosome marker (Ph-chromosome) as well as of the corresponding molecular marker (BCR-ABL fusion transcripts) provides suitable and precise tools to monitor the burden of the disease present at diagnosis and that of the residual disease present at specific time points during treatment. A huge number of studies have clearly demonstrated that in CML cytogenetic and molecular responses are strictly correlated to the final outcome of the patients and the correct use of standardized methods to assess the achievement of specific degrees of disease reduction at specific time points during treatment has become an essential part of proper clinical management of CML. The target to be achieved and the corresponding "optimal response" definition are however evolving, and at least for some patients, they may be represented not only by best possible overall survival (OS) but also by the possibility to discontinue the tyrosine-kinase inhibitor (TKI) treatment and therefore to live in a treatment-free remission (TFR) status. Therefore, at least for some patients, deep degrees of molecular response, as MR(4) and MR(4.5), whose precise definition has been recently introduced and that are prerequisites to try to discontinuation, are becoming the target to be achieved even in common clinical practice. As a fast initial decline of the disease burden after therapy start may be highly predictive for the final outcome of patients not only in terms of progression-free survival (PFS) and of PS but also in terms of possibility of achieving deep molecular responses, a more intense and punctual monitoring of the response of CML patients during the first 6 months of TKI therapy is now recommended by the more recent versions of the European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN) guidelines, as this represents the major driver to decide therapy.

Imatinib has represented a revolution in the treatment of chronic myeloid leukemia (CML), inducing an overall survival never seen with previous therapies. However, with the commonly used dosage of 400 mg, one third of the treated patients does not reach the criteria associated with an optimal outcome and could potentially benefit from a different treatment strategy. Several trials exploring modified imatinib-based treatments or second-generation tyrosine-kinase as front-line therapy have been performed. In some studies, high-dose (800 mg per day) or dose-adapted imatinib or imatinib plus interferon was reported to be able to induce better cytogenetic and molecular responses compared with standard-dose imatinib, although no improvements in progression-free survival (PFS) or overall survival (OS) have been so far reported. At the moment, these approaches are still considered investigational. On the other side, on the basis of their capacity to induce very fast and deep molecular responses, including major molecular responses (MMRs) and the newly defined very deep molecular responses MR⁴ and MR(4.5), and to prevent at least part of the early progressions to AP/BC that still occur during the first 2-3 years from diagnosis, dasatinib and nilotinib have been approved and registered by FDA and EMA as the first-line therapy for CML patients, opening the possibility to use different therapeutic strategies for newly diagnosed CML patients and a consequent intense debate among hematologists.

Introduction: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the translocation t(9;22), coding for the chimeric protein BCR-ABL. The development of BCR-ABL tyrosine kinase inhibitors (TKIs) has dramatically revolutionized and improved CML therapy. However, TKI-based therapy faces a major challenge: the insensitivity of CML leukemic stem cells (LSCs) to TKIs. In particular, while CML progenitor cells and differentiated cells are oncogene addicted, BCR-ABL tyrosine kinase is dispensable for CML LSC survival and maintenance. Notably, in CML, additional cellular mechanisms promote LSC survival and maintenance, rendering these cells able to survive even in the presence of TKI and to eventually promote relapse., Areas Covered: This review will focus on the mechanisms of LSC insensitivity to TKI and on the strategies to obtain synthetic lethality with combination therapies., Expert Opinion: Several pathways have been proposed to promote LSC maintenance and described as ideal targets to induce CML LSC exhaustion in combination with TKI. Ongoing clinical trials designed to target some of these pathways will assess which molecular target is relevant for in vivo human LSC survival in a new 'stem-cell targeting' perspective.

Background: A large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries., Patients and Methods: To describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75 years were retrospectively analyzed using data collected from 31 institutions in Italy., Results: The median age at imatinib start was 78.6 years [interquartile range (IR) 76.3-81.4], median time from diagnosis to imatinib start was 1.2 months (IR 0.5-3.7). The starting dose of imatinib was 400 mg/day in 144 patients (68.2 %), >400 mg/day in 4 patients (2.0 %), and <400 mg/day in 63 patients (29.8 %); overall, 94 patients (44.5 %) needed a dose reduction and 27 (12.7 %) discontinued imatinib for toxicity. Grade 3-4 hematologic and extrahematologic toxicities were observed in 40 (18.9 %) and 45 (21.3 %) patients, respectively. After a median observation of 29.8 months (IR 13.0-55.6), 203/211 patients had at least 6 months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2 %) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4 %) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5 %). Among the 129 patients with CCyR, 95 (46.7 %) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase (p = 0.001) and grade 3-4 extrahematologic toxicity (p = 0.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase (p = 0.026), grade 3-4 extrahematologic toxicity (p = 0.007), and lower initial dose of imatinib (p = 0.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6 % (95 % CI 88.7-96.5) and 78.0 % (95 % CI 71.2-84.8), respectively., Conclusions: Results from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies.

We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+), BCR-ABL-positive patients aged 65 years or older who had been treated with IM for more than 2 years and who were in stable complete cytogenetic response (CCgR) and major molecular response (MMR) were enrolled in a single-arm study to test the effects of a policy of intermittent IM (INTERIM) therapy for 1 month on and 1 month off. With a minimum follow-up of 4 years, 13 patients (17%) lost CCgR and MMR and 14 (18%) lost MMR only. All these patients resumed continuous IM and all but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase or developed clonal chromosomal abnormalities in Ph+ cells or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting >2 years), the policy of INTERIM treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). This trial was registered at www.clinicaltrials.gov as NCT 00858806.

To assess the most important features and clinical impact of pleural effusions, which are a common toxicity during dasatinib treatment and often impair its high efficacy, 172 unselected consecutive patients with chronic myelogenous leukaemia in chronic phase treated in 27 Italian centres, with dasatinib when aged >60 years for resistance/intolerance to imatinib, were examined. During treatment, 52/172 patients (30.2%) presented pleural effusion, which was grades 1-2 in 38 patients and grades 3-4 in 14 patients (8.1% of the entire cohort of patients), according to the WHO scale; in 14/52 patients (26.9%), there was a concomitant pericardial effusion. Pleural effusion was recurrent in 25/52 patients (48.0%). Median time from dasatinib to first pleural effusion was 11.0 months (interquartile range 3.6-18.6). Eleven patients (6.4%) required permanent dasatinib discontinuation. Only presence of concomitant pulmonary disease ( p = 0.035) and initial daily dose of dasatinib (140 mg vs 100 mg, p = 0.014) were significantly associated with pleural effusions. There were no differences among patients with or without pleural effusions as concerns response rates and overall survival. Pleural effusions were common in our unselected 'real-life' population of elderly patients but were clinically manageable and did not seem to affect treatment results., (Copyright © 2012 John Wiley & Sons, Ltd.)

There have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third-line alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third-line tyrosine kinase inhibitor therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32 of 82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.

To assess the impact of BCR-ABL kinase domain mutations on dasatinib response in elderly chronic myeloid leukemia (CML) patients, we analyzed the outcome of 76 individuals aged >60 affected by imatinib-resistant chronic-phase CML. We found that 36 cases (47 %) displayed mutations before dasatinib. Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. Our data suggest that, in elderly patients, detection of BCR-ABL mutations negatively affects response to dasatinib.

The prognosis of Philadelphia positive (Ph+) chronic myeloid leukemia (CML) has been revolutionized since the discovery of the pathogenetic role of BCR-ABL and the invention of tyrosine kinase inhibitors (TKIs). With a follow-up of 8 years, patients had an OS of 85 % and, with second generation TKIs, dasatinib and nilotinib, almost 50 % of the resistant patients gained a remission with an OS over 90 % at 2 years. Currently the challenge is preventing resistance leading to progression to advance phases that have still few chances of effective treatment. Another objective, derived from the needs of our patients, beside the pride of the scientist, is the discontinuation of the treatment. Second generations TKIs applied to the first line setting seem to be a good option either to avoid progression and to achieve deeper rates of molecular response, necessary for the cure.

Vigilant monitoring of a patient's response to current treatment is imperative to the management of chronic myeloid leukemia (CML). Early identification of treatment failure may increase the probability that alternative therapy will be effective. This review discusses the use of molecular monitoring in the timely detection of failure of imatinib treatment. Changes in the levels of BCR-ABL transcripts are predictive of response or relapse. Patients achieving a major molecular response (MMR) within 12 months of treatment may experience longer cytogenetic remission. Accumulating evidence also suggests that lower transcript levels observed ≤ 6 months after the start of treatment are associated with improved patient outcomes. For patients with primary or secondary imatinib resistance (or intolerance), dasatinib or nilotinib may be prescribed. These agents have demonstrated activity in patients harboring imatinib-resistant BCR-ABL mutations, except for the T315I substitution., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In patients with chronic myelogenous leukemia (CML) treated at diagnosis with the standard therapy consisting of imatinib, 400 mg once daily, the failure to achieve a complete cytogenetic response (CCyR) within 12 months from the start of therapy has been shown to be associated with an increased risk of progression and an overall inferior survival. Experts of the European LeukemiaNet and NCCN have indicated what degrees of hematologic, cytogenetic, and molecular responses should be expected at definite time points for patients with CML to have the highest probability of experiencing the final optimal response, defined as the achievement of at least a complete hematologic response with a minor cytogenetic response after 3 months; at least a partial cytogenetic response after 6 months; at least a CCyR after 12 months; and a major molecular response after 18 months of therapy. The last opportunity for a CCyR has been established at 18 months. Because the residual probability of attaining a CCyR is reduced for patients who do not experience a complete hematologic response by 3 months, any cytogenetic response by 6 months, or a major cytogenetic response by 12 months, these conditions are considered treatment failures. At this point, a change in therapy is highly recommended, such as second-line treatment with the second-generation tyrosine kinase inhibitors nilotinib or dasatinib and, in specific situations, a stem cell transplant. The loss of any grade of previously achieved cytogenetic response at any time point is also considered an imatinib failure demanding a change of therapy. Finally, intermediate gradations of response exist between optimal response and failure in which, although not totally compromised, the possibilities of achieving an optimal response later are decreased. The best therapeutic strategies to be followed in these intermediate situations, called suboptimal responses, have not been clearly established and are still under clinical investigation, but for the moment, a change of therapy is not required.

Background: Comorbidities may affect survival and choice of treatment among cancer patients. In fact, comorbidities have been identified as significant determinants of response to therapy in older patients with acute myeloid leukemia, breast cancer, head and neck cancer, and lung cancer. The Charlson comorbidity index and adult comorbidity evaluation-27 are lists of comorbidities with a weight assigned from 1 to 6 for the former and from 0 to 3 for the latter score, derived from relative risk estimates of a proportional hazard regression model using clinical data., Design and Methods: We retrospectively evaluated the Charlson index and adult comorbidity evaluation-27 score in a cohort of 125 elderly (> 60 years) patients with chronic phase chronic myeloid leukemia who received dasatinib after showing resistance or intolerance to imatinib with the aim of establishing associations between comorbidities and the development of pleural effusions or compliance with the drug treatment., Results: We found a significant association between the Charlson index as well as the adult comorbidity evaluation-27 score and the rate of drug reduction or suspension: with regards to the Charlson index, 49% of score 0 patients had a dose reduction compared to 63% of patients with score 1, 74% of those with score 2 and 100% of patients with score 3-5 (P=0.03); with regards to the adult comorbidity evaluation-27 score, 45% of patients had score 0-1 and 69% of patients with score 2-3 had a dose reduction. Of the 65 patients with Charlson score 0, 29% had at least one suspension of treatment (79% for hematologic and 21% for non-hematologic toxicity), compared to 46% of patients with score 1 (37% for hematologic and 69% for non-hematologic toxicity), 58% of patients with score 2 (36% for hematologic and 64% for non-hematologic toxicity) and 100% of patients with score 3 or 4 (all patients for both types of toxicity). High adult comorbidity index-27 scores identified patients at high risk of grade 3/4 hematologic toxicity. Forty-one patients (32.8%) experienced pleural effusion during treatment: the highest scores for both indices were associated with an increased risk of pleural effusions., Conclusions: In elderly patients with chronic myeloid leukemia treated with dasatinib, the rate of drug reduction or suspension and the incidence of pleural effusions seem to be associated with the presence of comorbidities: stratification according to the Charlson index and adult comorbidity evaluation-27 score before dasatinib therapy may enable the identification of patients at risk of major toxicities.

Second (2nd)-generation tyrosine kinase inhibitors (TKI) (dasatinib, nilotinib) are effective in patients with all phases of chronic myeloid leukaemia (CML). Dose reductions and treatment interruptions are frequently required due to toxicity, but their significance is unknown. We analysed the impact of dose reductions/interruptions and dose intensity of 2nd-generation TKI on response and survival. A total of 280 patients with CML (all phases) were analysed. Dose reductions were considered when the daily dose was below the standard dose. Dose intensity was determined based on the percentage of the ideal dose intensity. Overall, 176 patients (63%) required treatment interruptions and/or dose reduction at least once during therapy. Dose reductions/interruptions, analysed as a time-dependent covariate, were associated with worse failure-free survival only in patients with untreated CML. Dose intensity analysis did not reveal a worse response or survival in patients who received a lower dose intensity (<100%) during therapy or during the first 6 months. In conclusion, dose reductions and treatment interruptions of 2nd generation TKI in patients with CML have a minimal impact in the response rate and survival of these patients. Further studies are required to determine whether there might be a minimum adequate dose of these agents.

Little is known regarding the activity of tyrosine kinase inhibitors (TKis) on chronic myeloid leukemia (CML) clonal evolution (CE). We treated 10 CE CML patients in either hematologic chronic (8 cases) or accelerated (2 cases) phase with imatinib or second generation TKi. Additional chromosomal abnormalities appeared during the course of disease in seven cases, being present at diagnosis in three. A total of 6/10 (60%) patients achieved complete cytogenetic remission (CCyR) with imatinib in 3-14 months. Major or complete molecular remission (CMR) was obtained in four CCyR patients after 21, 25, 22, and 12 months, as well as in a fifth patient who started nilotinib because of suboptimal response after 75 months of imatinib treatment. One patient received nilotinib due to imatinib intolerance after 56 months of therapy while on CMR, and maintained such status. After a median follow-up of 82 months (range, 3-116), six patients are alive, five of which are in continuous CCyR while one patient is in his third CCyR on dasatinib after relapsing on imatinib and nilotinib. Five patients are in complete (four) or major (one) molecular remission, ongoing at 3, 48, 61, 95, and 96 months, on imatinib (three) or nilotinib (two). Although a small number of patients was studied, our results suggest that long-term cytogenetic and molecular remission can be achieved in CML CE patients with TKis treatment., (Copyright 2010 Elsevier Inc. All rights reserved.)

Second-generation tyrosine kinase inhibitors are effective in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Occasionally, patients with Ph(+) ALL, or accelerated phase (AP) or blast phase (BP) CML achieve a major cytogenetic response (MCyR) but not a complete hematologic response (CHR). We analyzed 126 patients with CML in AP or BP, or with Ph(+) ALL treated with dasatinib or nilotinib after imatinib failure. Twenty patients received sequential treatment with both dasatinib and nilotinib for a total of 146 instances. CHR and MCyR rates were 54% and 37%, respectively in AP, 17% and 39% in BP, and 33% and 50% in Ph+ ALL. Failure to achieve a CHR at the time of achievement of a MCyR was associated with an inferior outcome, similar to that of patients without a MCyR (2-year survival rate, 37% and 35%, respectively). In contrast, patients with MCyR and concomitant CHR had a 77% 2-year survival rate. Twelve of 29 patients with MCyR without concomitant CHR later achieved a CHR; the 2-year survival rate for these patients was 55% compared with 22% for those who never achieved a CHR. These results suggest that achievement of a MCyR without concomitant CHR is associated with poor outcome.

Imatinib is now established as the gold standard first-line therapy for patients with chronic myeloid leukemia (CML). Responses to imatinib are superior to those seen with interferon alfa and also occur earlier, demonstrating a stronger and deeper response to therapy. Imatinib therapy also provides long-term clinical benefit and outcomes, with improved progression-free survival (PFS) and overall survival (OS) compared with historical controls, at 6 years of follow-up. Recent data show that annual event rates decline over time with imatinib therapy, suggesting that long-term disease control is possible in continuously responding patients. Despite these treatment successes, new strategies are continually being evaluated to maximize responses to imatinib and ensure the best treatment outcomes for all patients. For example, high-dose imatinib therapy, with doses up to 800 mg/d, has been shown to improve response rates. Prospective, randomized trials are ongoing to assess the benefits of high-dose imatinib therapy and determine whether it extends PFS and OS compared with standard-dose imatinib.

The successful introduction of the tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with chronic myeloid leukemia (CML). Imatinib therapy induces high rates of complete cytogenetic and major molecular responses, and improves survival in CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and over 80% achieve a complete cytogenetic response. With 7 years of follow-up, the results are still very favorable, resulting in a major change in the natural history of the disease. Resistance to imatinib represents a clinical challenge. Although some clinical and biologic features have been found to be associated with a lower probability of response to imatinib, at present no precise markers allowing for the prediction of outcome for individual patients exist. The most common mechanisms of resistance to imatinib include BCR-ABL kinase domain mutations, amplification, and overexpression of the BCR-ABL oncogene, and clonal evolution with activation of additional transformation pathways. These mechanisms are eventually caused by the genomic instability, which characterizes the Philadelphia chromosome-positive clone. Several approaches to overcome resistance have been proposed. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new therapeutic agents that might overcome this resistance. Novel targeted agents designed to overcome imatinib resistance include second-generation TKIs such as dasatinib, nilotinib, bosutinib, bafetinib, and others. Other approaches are exploring combination therapy, with agents affecting different oncogenic pathways, and immune modulation. Herein, we review some of these targeted therapies, particularly those for which clinical data are already available.