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1.  Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia? 
Hematology Reports  2011;3(3):e29.
The outcome and quality of life of chronic myeloid leukemia (CML) patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs). Currently, hematopoietic stem cell transplantation (HSCT) is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombo-cytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.
doi:10.4081/hr.2011.e29
PMCID: PMC3269798  PMID: 22593820
chronic myeloid leukemia; tyrosine kinase inhibitor; thrombocytopenia; HSCT.
2.  Potential of ponatinib to treat chronic myeloid leukemia and acute lymphoblastic leukemia 
OncoTargets and therapy  2013;6:1111-1118.
Development of BCR-ABL tyrosine kinase inhibitors (TKIs) have improved outcomes for patients diagnosed with chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. However, resistance or intolerance to these TKIs still leaves some patients without many treatment options. One point mutation in particular, the T315I mutation, has been shown to be resistant to first and second generation TKIs. The third generation TKI, ponatinib, may provide an option for these patients. Ponatinib (Iclusig®), an orally available, pan-tyrosine kinase inhibitor has a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. A Phase II study evaluated ponatinib in patients who were resistant or intolerant to nilotinib or dasatinib or patients who had the T315I mutation. In the Phase II study, ponatinib produced a major cytogenetic response in 54% of chronic phase chronic myeloid leukemia patients. It further achieved major hematologic response in 52% of patients in the accelerated phase, 31% of patients in the blast phase, and 41% of Philadelphia chromosome positive acute lymphoblastic leukemia patients. Ponatinib also showed efficacy in patients with the T315I mutation. Serious adverse events included arterial thrombosis, hepatotoxicity, cardiovascular risks, pancreatitis, hemorrhage, fluid retention, myelosuppression, rash, abdominal pain, and embryo–fetal toxicity. Due to the risk of these adverse events and potential drug interactions, the use of ponatinib must be carefully weighed against the benefits in treating patients who have limited treatment options.
doi:10.2147/OTT.S36980
PMCID: PMC3754816  PMID: 23986642
BCR-ABL; tyrosine kinase inhibitor; TKI; T315I; Philadelphia chromosome
3.  The development of dasatinib as a treatment for chronic myeloid leukemia (CML): from initial studies to application in newly diagnosed patients 
Purpose
Dasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI) designed as a prototypic short-acting BCR–ABL-targeted TKI that inhibits BCR–ABL with greater potency compared with imatinib, nilotinib, bosutinib, and ponatinib and has been shown to have potential immunomodulatory effects. Dasatinib is approved for the treatment of all phases of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to prior imatinib treatment and first-line treatment for CML in chronic phase. In this article, the development of dasatinib as a treatment for patients with CML is reviewed.
Methods
This is a review of the relevant literature regarding dasatinib development in CML (2003–2013).
Results
Dasatinib demonstrates efficacy against most BCR–ABL mutations arising during imatinib therapy and is effective in treating patients with imatinib resistance due to other mechanisms. Randomized trial data show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses correlated with improved longer-term outcomes. Dasatinib has a generally acceptable safety profile, with most adverse events (AEs) proving manageable and reversible. Cytopenias are commonly observed with dasatinib, and some nonhematologic AEs including pleural effusion have been consistently reported.
Conclusion
Dasatinib is an effective treatment option for patients with CML.
doi:10.1007/s00432-013-1488-z
PMCID: PMC3825579  PMID: 23942795
Dasatinib; Chronic myeloid leukemia; First-line treatment; Second-line treatment; Side effects; Early response
4.  Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia 
Journal of Blood Medicine  2012;3:139-150.
Chronic myeloid leukemia (CML) is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+) chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs) exerting their effect against the oncogenic breakpoint cluster region (BCR)-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients compared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.
doi:10.2147/JBM.S29132
PMCID: PMC3503471  PMID: 23180974
drug resistance; tyrosine kinase inhibitors; chronic myeloid leukemia; imatinib; BCR/ABL
5.  BCR-ABL mutation testing to predict response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia 
PLoS Currents  2010;2:RRN1204.
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Although randomized evidence demonstrates that imatinib (a commercially available TKI) prolongs event–free survival in patients with CML, some patients develop imatinib intolerance or resistance. In addition, imatinib is less effective in patients who have progressed to more advanced disease stages, such as accelerated phase and blastic phase CML. For these reasons, 2nd generation TKIs that can inhibit the BCR-ABL protein more effectively or target additional disease mechanisms have been developed. Two such drugs have also been approved for clinical use by the FDA, nilotinib and dasatinib. Resistance to TKI treatment is thought to be mediated through various mechanisms, the most common of which is BCR-ABL1 mutations. Testing for mutations in BCR-ABL1 may predict lack of response to imatinib or may inform the choice between alternative TKIs.
doi:10.1371/currents.RRN1204
PMCID: PMC3001986  PMID: 21188137
6.  BCR-ABL mutation testing to predict response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia 
PLoS Currents  2011;2:RRN1204.
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Although randomized evidence demonstrates that imatinib (a commercially available TKI) prolongs event–free survival in patients with CML, some patients develop imatinib intolerance or resistance. In addition, imatinib is less effective in patients who have progressed to more advanced disease stages, such as accelerated phase and blastic phase CML. For these reasons, 2nd generation TKIs that can inhibit the BCR-ABL protein more effectively or target additional disease mechanisms have been developed. Two such drugs have also been approved for clinical use by the FDA, nilotinib and dasatinib. Resistance to TKI treatment is thought to be mediated through various mechanisms, the most common of which is BCR-ABL1 mutations. Testing for mutations in BCR-ABL1 may predict lack of response to imatinib or may inform the choice between alternative TKIs.
doi:10.1371/currents.RRN1204
PMCID: PMC3001986  PMID: 21188137
7.  Evolution of Therapies for Chronic Myelogenous Leukemia 
Cancer journal (Sudbury, Mass.)  2011;17(6):465-476.
The clinical outcome for patients with chronic myeloid leukemia (CML) has changed dramatically in the past 15 years. This has been due to the development of tyrosine kinase inhibitors (TKI), compounds which inhibit the activity of the oncogenic BCR-ABL1 protein. Imatinib was the first TKI developed for CML, and it led to high rates of complete cytogenetic responses and improved survival for patients with this disease. However, about 35% of patients in chronic phase treated with imatinib will develop resistance or intolerance to this drug. The recognition of the problem of imatinib failure led to the design of 2nd-generation TKI (dasatinib, nilotinib and bosutinib). These drugs are highly active in the scenario of imatinib resistance or intolerance. More recently, both nilotinib and dasatinib were approved for frontline use in patients with chronic phase CML. Ponatinib represents the last generation of TKI, and this drug has been developed with the aim of targeting a specific BCR-ABL1 mutation (T315I) which arises in the setting of prolonged TKI therapy and leads to resistance to all commercially available TKI. Parallel to the development of specific drugs for treating CML, major advances were made in the field of disease monitoring and standardization of response criteria. In this review we summarize how therapy with TKI for CML has evolved over the last decade.
doi:10.1097/PPO.0b013e31823dec8d
PMCID: PMC3243359  PMID: 22157290
Chronic Myelogenous Leukemia; BCR-ABL1; Tyrosine Kinase Inhibitors; Imatinib; Dasatinib; Nilotinib; Bosutinib; Ponatinib
8.  Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells 
Stem Cells International  2013;2013:724360.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML.
doi:10.1155/2013/724360
PMCID: PMC3725740  PMID: 23935640
9.  An approach to the management of chronic myeloid leukemia in British Columbia 
Current Oncology  2008;15(2):90-97.
Chronic myeloid leukemia (cml) is a myeloproliferative disorder whose therapy has changed dramatically since the late 1990s. With the introduction of the tyrosine kinase inhibitor (tki) imatinib mesylate, the treatment outcomes for patients with cml have improved markedly, and hematopoietic stem-cell transplantation is no longer routinely offered as first-line therapy for most patients in chronic phase.
However, resistance to tki therapy is increasingly being recognized, and alternative therapy is needed for this group of patients. In addition, the development of models predicting response to tki therapy is desired, so that appropriate treatment strategies can be used for individual patients. The present report serves to outline the approach to the treatment of cml in British Columbia and to highlight areas of ongoing research.
PMCID: PMC2365478  PMID: 18454182
Chronic myeloid leukemia; treatment guidelines
10.  Second-Generation Tyrosine Kinase Inhibitors (Tki) as Salvage Therapy for Resistant or Intolerant Patients to Prior TKIs 
With the advent of target therapies, imatinib became the mainstay for treatment of chronic myeloid leukemia. However, despite the brilliant results obtained with this drug, more than 30% of patients discontinue therapy in long-term due to several reasons, including failure and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) are more potent drugs and have expanded inhibition against a broad spectrum of mutations resistant to imatinib. Both nilotinib and dasatinib have demonstrated in vitro and in vivo clinical activity against different types of mutations and various forms of resistance. However, patients with T315I mutation do not obtain an advantage from these drugs and a third generation inhibitor ponatinib, a pan-BCR drug, was tested with significant results. In this review, we report the results of second-and third-generation TKIs tested as second or third line therapy in patients resistant and/or intolerant to previous inhibitors.
doi:10.4084/MJHID.2014.003
PMCID: PMC3894843  PMID: 24455112
11.  Interpretation of cytogenetic and molecular results in patients treated for CML 
Blood reviews  2011;25(3):139-146.
The International Randomized Study of Interferon vs. STI571 (IRIS) trial that investigated the use of the tyrosine kinase inhibitor (TKI) imatinib (versus interferon) changed the treatment and outcome of chronic myeloid leukemia (CML). Long-term follow-up of IRIS patients has defined response parameters and methods of tracking residual disease with cytogenetic testing of bone marrow metaphases and molecular monitoring of BCR-ABL transcripts using quantitative reverse-transcriptase polymerase chain reaction. Cytogenetic and molecular responses are now considered useful surrogates for long-term outcome. Early and robust response to imatinib predicts positive long-term outcomes. However, 15–25% of patients fail initial treatment or become intolerant of imatinib and need increased doses or alternate treatment. Second-line treatment with the second-generation TKIs nilotinib and dasatinib have resulted in favorable rates of progression-free survival (PFS) and overall survival. Data from the ENESTnd (nilotinib) and DASISION (dasatinib) trials in newly diagnosed chronic-phase CML patients demonstrated more robust and rapid complete cytogenetic (77–80%) and major molecular responses (43–46%) at 12 months compared with imatinib (65–66% and 22–28%). The relationship between a complete cytogenetic response at 12 months and long-term PFS supports a role for second-generation TKIs as first-line treatment of newly diagnosed chronic-phase CML.
doi:10.1016/j.blre.2011.02.001
PMCID: PMC3071443  PMID: 21419537
Chronic myeloid leukemia; cytogenetic response; molecular response; dasatinib; nilotinib; imatinib
12.  The occurrence and management of fluid retention associated with TKI therapy in CML, with a focus on dasatinib 
Tyrosine kinase inhibitors (TKIs) like dasatinib and nilotinib are indicated as second-line treatment for chronic myeloid leukemia resistant or intolerant to the current first-line TKI imatinib. These are agents are well tolerated, but potent and as such should be monitored for potentially serious side-effects like fluid retention and pleural effusions. Here we present key clinical trial data and safety considerations for all FDA approved TKIs in context for effective management of fluid retention and pleural effusions. Altering the dasatinib regimen from 70 mg twice daily to 100 mg daily reduces the risk of pleural effusion for patients taking dasatinib. Should pleural effusion develop, dasatinib should be interrupted until the condition resolves. Patients with a history of pleural effusion risk factors should be monitored closely while taking dasatinib. Patients receiving imatinib and nilotinib are not without risk of fluid retention. All patients should also be educated to recognize and report key symptoms of fluid retention or pleural effusion. Pleural effusions are generally managed by dose interruption/reduction and other supportive measures in patients with chronic myeloid leukemia receiving dasatinib therapy.
doi:10.1186/1756-8722-2-46
PMCID: PMC2785832  PMID: 19909541
13.  Using 2nd generation tyrosine kinase inhibitors in frontline management of chronic phase chronic myeloid leukemia 
South Asian Journal of Cancer  2014;3(1):87-91.
Choices in medicine come with responsibility. With several TKI's (Tyrosine kinase inhibitors) available for front-line management of CML (Chronic Myeloid Leukemia), an astute clinician has to personalise, rationalise and take a pragmatic approach towards selection of the best drug for the ‘patient in question’. Though it is hotly debated as to which TKI will triumph, the truth of this debate lies in individualising treatment rather than a general ‘all size fits all’ approach with imatinib. I personally believe that the second generation TKI's will suit most patient clinical profiles rather than prescribing imatinib to all and I have strived to make a strong case for them in front line treatment of CML. Though Imatinib may remain the first line choice for some patients, my efforts in this debate are mainly geared towards breaking the myth that imatinib is the sole ‘block buster’ on the CML landscape
doi:10.4103/2278-330X.126566
PMCID: PMC3961879  PMID: 24665456
Chronic myeloid leukemia; tyrosine kinase inhibitor; debate
14.  Therapy of Chronic Myeloid Leukemia: Twilight of the Imatinib Era? 
ISRN Oncology  2014;2014:596483.
Chronic myeloid leukemia (CML) results from the clonal expansion of pluripotent hematopoietic stem cells containing the active BCR/ABL fusion gene produced by a reciprocal translocation of the ABL1 gene to the BCR gene. The BCR/ABL protein displays a constitutive tyrosine kinase activity and confers on leukemic cells growth and proliferation advantage and resistance to apoptosis. Introduction of imatinib (IM) and other tyrosine kinase inhibitors (TKIs) has radically improved the outcome of patients with CML and some other diseases with BCR/ABL expression. However, a fraction of CML patients presents with resistance to this drug. Regardless of clinical profits of IM, there are several drawbacks associated with its use, including lack of eradication of the malignant clone and increasing relapse rate resulting from long-term therapy, resistance, and intolerance. Second and third generations of TKIs have been developed to break IM resistance. Clinical studies revealed that the introduction of second-generation TKIs has improved the overall survival of CML patients; however, some with specific mutations such as T315I remain resistant. Second-generation TKIs may completely replace imatinib in perspective CML therapy, and addition of third-generation inhibitors may overcome resistance induced by every form of point mutations.
doi:10.1155/2014/596483
PMCID: PMC3929284  PMID: 24634785
15.  Navigating the road towards optimal initial therapy for chronic myeloid leukemia 
Current opinion in hematology  2011;18(2):89-97.
Purpose of review
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) and are now widely accepted as the initial therapy of choice in this disease, supplanting interferon and allogeneic stem cell transplantation. There are currently three drugs approved by the Food and Drug Administration (FDA) for front-line treatment of CML: imatinib, nilotinib, and dasatinib. A fourth drug, bosutinib, is expected to win FDA approval in 2011. The goal of this review is to summarize the most recent information on initial treatment of CML and to aid clinicians in managing newly diagnosed CML patients.
Recent findings
Phase III studies comparing imatinib with nilotinib or dasatinib in newly diagnosed CML were published in July 2010, leading to accelerated FDA approval for both of these “second-generation” TKIs for initial therapy of CML. There are significant differences between the agents in terms of frequency and rate of responses, progression-free survival, and side effects. However, the follow-up period on these trials is short, and there are as yet no significant differences in overall survival. Guidelines for monitoring CML patients on TKI therapy have been recently revised.
Summary
Management of newly diagnosed CML patients in the coming decade will begin to resemble antibiotic treatment of infection, with therapy individualized based on patient risk factors, co-morbidities, and tolerability. In addition, the cost of therapy will emerge as an important consideration as generic imatinib becomes available in 2015. In this context, clinical trials to guide decision-making in newly diagnosed CML patients are needed.
doi:10.1097/MOH.0b013e32834399a5
PMCID: PMC3496274  PMID: 21252655
Chronic myelogenous leukemia; bosutinib; dasatinib; imatinib; nilotinib; tyrosine kinase inhibitor
16.  Chronic myeloid leukemia therapy in the era of tyrosine kinase inhibitors. The first molecular targeted treatment  
Journal of Medicine and Life  2010;3(2):162-166.
Chronic Myeloid Leukemia is the first malignant disorder with a specific genetic abnormality in the background. Known as a disease with an inexorable progression to acute leukemia for many years, its natural history has been dramatically improved by the use of tyrosine kinase inhibitors (TKI). They represent the first molecular targeted therapy addressed to a neoplastic disorder. From these new classes of drugs, Imatinib was the first drug ever used, and it remains the standard therapy for patients in chronic phase with CML, having a global survival of 86%, for 7 years. The 2nd generation of TKI (Dasatinib, Nilotinib) is indicated for the patients who are refractory or intolerant to Imatinib. The other TKI have good promises to be efficient on the mutations of BCR–ABL transcript, especially to non–responsive T315I mutation.
The new era of molecular target therapy is a new hope of life for all cancer patients.
PMCID: PMC3019054  PMID: 20968202
chronic myeloid leukemia; tyrosine kinase inhibitors; molecular target; BCR–ABL translocation
17.  Severe toxicity of skin rash, fever and diarrhea associated with imatinib: case report and review of skin toxicities associated with tyrosine kinase inhibitors 
Chronic myeloid leukemia (CML) is characterized by a Philadelphia chromosome which contains an oncogene, bcr-abl. This oncogene encodes a tyrosine kinase which is constitutively activated. Imatinib, a tyrosine kinase inhibitor (TKI), has been widely used in the treatment of CML. Dasatinib and nilotinib were recently approved for the treatment of CML. Other TKIs, such as bosutinib, erlotinib, and sunitinib, are under study for the treatment of CML as well as other hematologic and solid malignancies. Skin rash has been reported as one of the most common side effects of the TKIs. Here we present a case of severe skin rash together with unusual symptoms of high fever and diarrhea induced by imatinib in a CML patient. The dermatologic toxicities from a variety of tyrosine kinase inhibitors are reviewed and general principles of management are also discussed.
PMCID: PMC2761170  PMID: 19920908
chronic myeloid leukemia; skin rash; tyrosine kinase inhibitor; imatinib
18.  Current Management of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors 
Turkish Journal of Hematology  2013;30(3):247-255.
The clinical outcomes and survival of tyrosine kinase inhibitor (TKI)-treated patients with chronic myeloid leukemia (CML) have been significantly improved. The aim of this editorial is to outline critical steps of TKI administration practices during the long-term clinical course of CML based on data obtained from randomized clinical trials and international recommendations. The efficacy of TKI treatment, TKI side effects, off-target complications, and long-term morbidities due to both the disease and the drug are common arguments in the management of CML. Complete hematological response, early complete cytogenetic response, faster major molecular response, and deeper, more durable molecular responses (MR4, MR4.5, MR5) are the ultimate goals for TKI-receiving patients with CML.
Conflict of interest:None declared.
doi:10.4274/Tjh.2013.0108
PMCID: PMC3878539  PMID: 24385803
Chronic myeloid leukemia; Tyrosine kinase inhibitor; Imatinib; Nilotinib; Dasatinib; Bosutinib; Ponatinib
19.  Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis 
British Journal of Cancer  2012;106(9):1475-1480.
Background:
A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity.
Methods:
Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan–Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model.
Results:
In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations.
Conclusion:
Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.
doi:10.1038/bjc.2012.89
PMCID: PMC3341863  PMID: 22441644
intolerance; kidney cancer; mTOR inhibitor; RAD001; VEGF-targeted therapy
20.  Variable Behavior of iPSCs Derived from CML Patients for Response to TKI and Hematopoietic Differentiation 
PLoS ONE  2013;8(8):e71596.
Chronic myeloid leukemia disease (CML) found effective therapy by treating patients with tyrosine kinase inhibitors (TKI), which suppress the BCR-ABL1 oncogene activity. However, the majority of patients achieving remission with TKI still have molecular evidences of disease persistence. Various mechanisms have been proposed to explain the disease persistence and recurrence. One of the hypotheses is that the primitive leukemic stem cells (LSCs) can survive in the presence of TKI. Understanding the mechanisms leading to TKI resistance of the LSCs in CML is a critical issue but is limited by availability of cells from patients. We generated induced pluripotent stem cells (iPSCs) derived from CD34+ blood cells isolated from CML patients (CML-iPSCs) as a model for studying LSCs survival in the presence of TKI and the mechanisms supporting TKI resistance. Interestingly, CML-iPSCs resisted to TKI treatment and their survival did not depend on BCR-ABL1, as for primitive LSCs. Induction of hematopoietic differentiation of CML-iPSC clones was reduced compared to normal clones. Hematopoietic progenitors obtained from iPSCs partially recovered TKI sensitivity. Notably, different CML-iPSCs obtained from the same CML patients were heterogeneous, in terms of BCR-ABL1 level and proliferation. Thus, several clones of CML-iPSCs are a powerful model to decipher all the mechanisms leading to LSC survival following TKI therapy and are a promising tool for testing new therapeutic agents.
doi:10.1371/journal.pone.0071596
PMCID: PMC3751925  PMID: 24058405
21.  Monitoring response and resistance to treatment in chronic myeloid leukemia 
Current Oncology  2011;18(2):e71-e83.
Chronic myeloid leukemia (cml) results from expression of the constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. Imatinib, a tyrosine kinase inhibitor (tki), is highly effective in the treatment of cml. However, some patients treated with imatinib will fail to respond, will respond suboptimally, or will relapse because of primary or acquired resistance or intolerance. Research activities focusing on the mechanisms that underlie imatinib resistance have identified mutations in the BCR-ABL gene, clonal evolution, and amplification of the BCR-ABL gene as common causes. Cytogenetic and molecular techniques are currently used to monitor cml therapy for both response and relapse. With multiple and more potent therapeutic options now available, monitoring techniques can permit treatment to be tailored to the individual patient based on disease characteristics—for example, according to BCR-ABL mutation profile or to patient characteristics such as certain comorbid conditions. This approach should benefit patients by increasing the potential for better long-term outcomes.
PMCID: PMC3070714  PMID: 21505592
Chronic myeloid leukemia; protein kinase inhibitors; imatinib; drug resistance; drug monitoring
22.  Chronic myeloid leukemia (CML): association of treatment satisfaction, negative medication experience and treatment restrictions with health outcomes, from the patient’s perspective 
Background
The availability of the tyrosine-kinase inhibitor (TKI), imatinib, and later introduction of second generation TKIs, dasatinib and nilotinib, have not only improved clinical outcomes of patients with chronic myeloid leukemia (CML), but also provide multiple therapeutic options for CML patients. Despite the widespread use of these oral therapies, little is known about the impact of different treatment regimens on patient-reported outcomes (PROs) among CML patients. The objective of this study was to assess the impact of patient-reported treatment restrictions and negative medication experiences (NMEs) on satisfaction and other health outcomes among patients with CML treated with oral TKIs.
Methods
Participants recruited from survey panels and patient networks in the United States (US) and Europe completed an online questionnaire. Respondents included adults (≥18 years) with chronic-phase CML currently on TKI treatment. Study variables included treatment difficulty (i.e., difficulty in following treatment regimens), CML dietary/dosing requirements, NMEs, and validated PROs assessing treatment satisfaction, health-related quality of life (HRQoL), activity impairment, and non-adherence. Structural equation models assessed associations among variables, controlling for covariates.
Results
303 patients with CML (US n=152; Europe n=151; mean age 51.5 years; 46.2% male) completed the questionnaire. Approximately 30% of patients reported treatment difficulties; treatment difficulty was higher among nilotinib (63.3%) than among dasatinib (2.6%) or imatinib (19.2%) treated patients (p<0.0001). Non-adherence was generally low; however, patients on nilotinib vs. imatinib reported missing doses more often (p<0.05). Treatment satisfaction was associated with significantly increased HRQoL (p<0.05) and lower activity impairment (p<0.01). NMEs were associated with decreased treatment satisfaction (p<0.01) and HRQoL (p<0.05), and greater activity impairment (p<0.01). Higher overall treatment restrictions were associated with greater treatment difficulty (p<0.001), which correlated with non-adherence (p<0.01).
Conclusions
Treatment satisfaction and NMEs are important factors associated with HRQoL among patients with CML. Increased treatment restrictions and associated difficulty may affect adherence with TKIs. Choosing a CML treatment regimen that is simple and conveniently adaptable in patients’ normal routine can be an important determinant of HRQoL and adherence.
doi:10.1186/1477-7525-11-167
PMCID: PMC3851879  PMID: 24099272
CML; Adherence; Quality of life; Treatment satisfaction; Treatment restrictions
23.  Monitoring the Response to Tyrosine Kinase Inhibitor (TKI) Treatment in Chronic Myeloid Leukemia (CML) 
The aim of oral tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is to get ideal hematological, cytogenetic, molecular responses at the critical time points. The depth of the response obtained with TKI and the time to achieve this response are both important in predicting the prognosis in patients with CML. The high efficacy of the TKI treatment of CML has prompted the need for accurate methods to monitor response at levels below the landmark of CCyR. Quantification of BCR-ABL transcripts has proven to be the most sensitive method available and has shown prognostic impact with regard to progression-free survival. European LeukemiaNet (ELN) molecular program harmonized the reporting of results according to the IS (International harmonization of Scale) in Europe. The aim of this review is to outline monitoring the response to optimal TKI treatment based on the ELN CML 2013 recommendations from the clinical point of view as a physician. Careful cytogenetic and molecular monitoring could help to select the most convenient TKI drug and to optimize TKI treatment. Excessive monitoring may have an economic cost, but failure to optimize TKI treatment may result in CML disease acceleration and death.
doi:10.4084/MJHID.2014.009
PMCID: PMC3894837  PMID: 24455118
24.  Effects of Ketoconazole on the Pharmacokinetics of Ponatinib in Healthy Subjects 
Journal of Clinical Pharmacology  2013;53(9):974-981.
Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in patients resistant or intolerant to prior TKIs. In vitro studies suggested that metabolism of ponatinib is partially mediated by CYP3A4. The effects of CYP3A4 inhibition on the pharmacokinetics of ponatinib and its CYP3A4-mediated metabolite, AP24567, were evaluated in a single-center, randomized, two-period, two-sequence crossover study in healthy volunteers. Subjects (N = 22) received two single doses (orally) of ponatinib 15 mg, once given alone and once coadministered with daily (5 days) ketoconazole 400 mg, a CYP3A4 inhibitor. Ponatinib plus ketoconazole increased ponatinib maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) compared with ponatinib alone. The estimated mean ratios for AUC0–∞, AUC0–t, and Cmax indicated increased exposures to ponatinib of 78%, 70%, and 47%, respectively; exposure to AP24567 decreased by 71%. Exposure to AP24567 was marginal after ponatinib alone (no more than 4% of the exposure to ponatinib). These results suggest that caution should be exercised with the concurrent use of ponatinib and strong CYP3A4 inhibitors and that a ponatinib dose decrease to 30 mg daily, from the 45 mg daily starting dose, could be considered.
doi:10.1002/jcph.109
PMCID: PMC3786320
BCR-ABL; ketoconazole; pharmacokinetics; ponatinib; tyrosine kinase inhibitor
25.  Effects of Ketoconazole on the Pharmacokinetics of Ponatinib in Healthy Subjects 
Journal of Clinical Pharmacology  2013;53(9):974-981.
Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia in patients resistant or intolerant to prior TKIs. In vitro studies suggested that metabolism of ponatinib is partially mediated by CYP3A4. The effects of CYP3A4 inhibition on the pharmacokinetics of ponatinib and its CYP3A4-mediated metabolite, AP24567, were evaluated in a single-center, randomized, two-period, two-sequence crossover study in healthy volunteers. Subjects (N = 22) received two single doses (orally) of ponatinib 15 mg, once given alone and once coadministered with daily (5 days) ketoconazole 400 mg, a CYP3A4 inhibitor. Ponatinib plus ketoconazole increased ponatinib maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) compared with ponatinib alone. The estimated mean ratios for AUC0–∞, AUC0–t, and Cmax indicated increased exposures to ponatinib of 78%, 70%, and 47%, respectively; exposure to AP24567 decreased by 71%. Exposure to AP24567 was marginal after ponatinib alone (no more than 4% of the exposure to ponatinib). These results suggest that caution should be exercised with the concurrent use of ponatinib and strong CYP3A4 inhibitors and that a ponatinib dose decrease to 30 mg daily, from the 45 mg daily starting dose, could be considered.
doi:10.1002/jcph.109
PMCID: PMC3781849  PMID: 23801357
BCR-ABL; ketoconazole; pharmacokinetics; ponatinib; tyrosine kinase inhibitor

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