Abruzzese biodrug

Reprinted from 2013, DOI 10.1007/s40259-013-0056-z ISSN: 1173-8804 (Print); 1179-190X (Online)

BioDrugs BIOTECHNOLOGY AND CLINICAL INNOVATION

Adis Drug Evaluation Second-Generation TKIs in CML

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BioDrugs DOI 10.1007/s40259-013-0056-z

REVIEW ARTICLE

Second-Generation Tyrosine Kinase Inhibitors in First-Line Treatment of Chronic Myeloid Leukaemia (CML) Elisabetta Abruzzese • Massimo Breccia Roberto Latagliata

•

© Springer International Publishing Switzerland 2013

Abstract Tyrosine kinase inhibitors (TKIs) have contributed to marked improvements in survival in patients with chronic myeloid leukaemia (CML). This article discusses the place of the second-generation TKIs dasatinib and nilotinib in the first-line treatment of CML and is based on published literature. The new agents are more potent and effective than imatinib. Data from pivotal clinical trials indicate that response to dasatinib and nilotinib is greater and more rapid than that to imatinib, resulting in a higher probability of patients achieving an optimal response to treatment. Differences between the newer agents with respect to patient groups for whom caution is advised, drug interaction potential, haematological toxicity, pulmonary toxicity, changes in the immune system and effects on laboratory parameters are discussed. With similar levels of efficacy, the choice of second-generation agents should be guided by the characteristics of the individual patient and the most suitable dosing regimen.

E. Abruzzese, M. Breccia and R. Latagliata contributed equally to the paper.

E. Abruzzese (&) Hematology, S. Eugenio Hospital, Tor Vergata University, P. le dell’Umanesimo 10, 00144 Rome, Italy e-mail: elisabetta.abruzzese@uniroma2.it M. Breccia Department of Cellular Biotechnology and Hematology, Sapienza University, Rome, Italy e-mail: breccia@bce.uniroma1.it R. Latagliata Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Via Benevento 6, Rome, Italy e-mail: rob.lati@libero.it

1 Introduction Chronic myeloid leukaemia (CML) is a hematopoietic stem cell disease characterised by the uncontrolled proliferation of white blood cells in the blood and bone marrow [1]. Caused by a translocation between chromosomes 9 and 22, the Philadelphia (Ph) chromosome is formed by the fusion of the breakpoint cluster region (BCR) and the Abelson murine leukaemia (ABL) genes [2–6]. The resulting BCR-ABL fusion gene leads to an ABL protein that forms a constitutively active tyrosine kinase protein, with cell-cycle deregulation [6].

Of all adult leukaemias, approximately 15 % are CML; the incidence is between one and two new cases/100,000/year [1, 6]. With the use of tyrosine kinase inhibitor (TKI) therapy, the all-cause annual mortality rate was reduced to 2 %, so that the prevalence of CML is increasing over time to reach a near plateau prevalence of 35 times the annual incidence [7].

CML is generally diagnosed in the middle-to-later stages of life, with 70 % of all diagnosed patients aged over 45 years.

Half of all patients are aged 65 years or older when diagnosed, indicating that advanced age and the inherent risk of concomitant diseases play a large role [8]. This aside, survival rates in patients with CML are increasing; in the early 1990s, the 5- and 10-year survival rates were 27 % and 9.5 %, respectively, while in the early 2000s these values increased to 49 % and 34 %, respectively [9]. More recently, estimated eventfree survival rates after 5 and 8 years of therapy with the TKI imatinib were 89 %and 81 %, respectively [10, 11]. The improved outcomes follow the advances in treatment modalities and the availability of more efficacious therapies [10].

1.1 Objective and Methods The objective of this article is to evaluate the place of second-generation TKIs in the first-line treatment of CML

E. Abruzzese et al.

through discussion of selected clinical data. The authors based their considerations on review of the data available in the literature in July 2012.

Only the large, pivotal studies of dasatinib and nilotinib were used in this review and they were identified in PubMed using the terms dasatinib OR nilotinib AND chronic myeloid leukaemia AND first-line. Published conference abstracts were also included and were identified using the same search terms in databases of three relevant international associations [American Society of Clinical Oncology, American Society of Hematology and European Haematology Association], which contain meeting abstracts from international congresses held in 2010–2013.

Reference lists of identified publications were also scanned for articles relevant to the topic and some references known to the author were included. Only studies in humans were included.

2 Treating Chronic Myeloid Leukaemia The first-line treatment of CML is at present mainly based on pharmacological therapy. The pharmacological treatment of CML initially employed therapies such as busulfan [12], hydroxyurea [13] or interferon-a (with or without cytarabine) [14, 15], but patient outcomes were greatly enhanced with the development of targeted therapy, such as the BCR-ABL TKI imatinib mesylate (Gleevec® or Glivec®) [16]. This drug was approved by the US FDA in 2001 for advanced-stage CML and as a first-line treatment in 2002 [6]. Imatinib is recommended by the National Comprehensive Cancer Network (NCCN) as the standard firstline treatment for newly diagnosed chronic-phase CML [6] and it is estimated that patients who respond to treatment may remain symptom free for at least 10 years [1], with overall survival rates of 86 % after 8 years [17]. Unfortunately, patients can become resistant or intolerant to imatinib. Primary resistance to imatinib exists in approximately 20 % of patients, while secondary resistance to imatinib develops in an additional 20 % of patients [1, 6].

2.1 Second-Generation Tyrosine Kinase Inhibitors (TKIs) More recently, second-generation TKIs have been developed to provide greater efficacy and tolerability: two are currently available for first-line therapy, dasatinib (Sprycel®, Bristol-Myers Squibb Company) and nilotinib (Tasigna®, Novartis). A third TKI, bosutinib (Bosulif®, Pfizer), has recently been approved by the FDA only for second- or later-line therapy and therefore falls outside the scope of this article and will not be discussed further.

Compared with imatinib, first-line therapy with both

dasatinib and nilotinib has been associated with a higher response rate, reduced disease progression and improved tolerability [18, 19].

Nilotinib is a highly selective molecule for the BCRABL tyrosine kinase, and binds to the inactive conformation of the protein. Constructed using a rational drug design, nilotinib was created to have a greater topographical fit with ABL. Nilotinib inhibits a number of kinases, such as KIT, platelet-derived growth factor (PDGFR) and a number of ABL mutations [20]. It does not inhibit SRCfamily kinases and is 30–50 times more potent than imatinib in imatinib-sensitive and imatinib-resistant cell lines [1, 6]. It was approved by the FDA in 2007 for the treatment of chronic- and accelerated-phase Ph and CML in adult patients resistant or intolerant to prior imatinib therapy and is now approved for use as first-line therapy [6]. Nilotinib must be taken twice daily under a fasting regimen because food increases drug exposure: it should be taken 2 h after a meal, and food must not be consumed for at least 1 h after administration. Additionally, inhibitors of cytochrome P450 (CYP) 3A4 (such as grapefruit juice) should be avoided [21].

Dasatinib inhibits ABL tyrosine kinase by binding to both the active and inactive forms of the ABL kinase domain [6]. It has a wide-ranging effect because of its activity against the SRC-family kinases and like nilotinib has activity against a number of other kinases, including KIT, PDGFR and ephrin receptor tyrosine kinases [1].

Furthermore, it has demonstrated in vitro and clinical efficacy against the majority of imatinib-resistant BCRABL mutations (except T315I and F317L.) [6] and is approved for the treatment of imatinib-resistant and imatinib-intolerant CML, Ph and acute lymphoblastic leukaemia and newly diagnosed Ph and CML [22]. Dasatinib is administered once daily and is not affected by food [23].

Dasatinib is a substrate and an inhibitor of CYP 3A4 and so caution should be taken when concomitantly administered with CYP3A4 inhibitors or inducers as this could alter the exposure to dasatinib and the concomitant drug [23].

2.2 Response to Second-Generation TKIs in Newly Diagnosed Patients Both dasatinib and nilotinib are considered by the NCCN as alternative treatment options to imatinib for patients with newly diagnosed CML. Additionally, intermediateand high-risk patients may benefit from these secondgeneration TKIs because of their improved outcomes in lowering the risk of disease progression [6]. This is based on two different international company-sponsored randomized trials in which second-generation TKIs were compared with imatinib in newly diagnosed CML patients [18, 19].

Second-Generation TKIs in CML

In the ENESTnd trial, nilotinib at two different doses (400 or 300 mg twice daily) was compared with imatinib 400 mg daily [19, 24], while in the DASISION trial dasatinib at the standard dose of 100 mg daily was compared with imatinib 400 mg daily [18].

Data from the ENESTnd trial demonstrated that complete cytogenic response (CcyR) at 12 months was achieved by significantly more nilotinib recipients (87 % of 300 mg twice daily and 85 % of 400 mg twice-daily groups, respectively) than imatinib recipients (77 %, all p \ 0.016) [19, 24, 25]. Furthermore, the cumulative incidence of a major molecular response (MMR) at 36 months was 73 % and 70 % for nilotinib 300 and 400 mg twice-daily groups, respectively, compared with 55 % for the imatinib group, while the cumulative incidence of molecular responses of BCR-ABLIS B 0.0032 (MR4.5) at the same time point was 32 %, 28 % and 15 %, respectively [25, 26].

Similarly, in the DASISION trial, CcyR was achieved at 12 months in 83 % of dasatinib recipients versus 72 % of imatinib recipients [18]. At 36-month follow-up, the DASISION trial reported that dasatinib was associated with higher rates of MMR (BCR-ABL B 0.1) than imatinib across all risk groups according to the Hasford score [27]. The proportion achieving MMR (BCR-ABL B 0.1) at 36 months was significantly higher in the dasatinib-treated group (68 %) compared with the imatinib-treated group (55 %) and was consistently higher across all Hasford risk categories [27]. Of those patients taking dasatinib who achieved MMR at 12 months, 97 % had maintained their MMR at 24 months, compared with 92 % of those taking imatinib [27]. The proportion of patients with MR4.5 was also greater in the dasatinib group versus the imatinib group (17 % vs. 9 %, respectively) [27].

Compared with imatinib, both nilotinib and dasatinib have demonstrated a faster time to achieving response. In the ENESTnd trial, the median time to MMR was 8.3 months for both doses of nilotinib versus 11 months for imatinib [25, 26]. In the DASISION trial, the median time to CCyR was 3.2 months in patients receiving dasatinib 100 mg once daily, compared with 6.0 months in patients receiving imatinib 400 mg once daily. The median time to MMR (BCR-ABL \ 0.1) was 21 months shorter with dasatinib than imatinib (15 vs. 36 months, respectively) [27].

In the ENESTnd trial, estimated 36-month rates of freedom from progression to AP/BC (on core treatment) were higher for nilotinib (99.3 % and 98.7 % for 300 and 400 mg) compared with imatinib (95.2 %). Estimated 36-month overall disease-related survival rates were higher for nilotinib than imatinib (98.1 % and 98.5 % vs. 95.2 %) while no difference was observed in the overall survival [26]. The probability of progressing to the accelerated or blast phase was significantly lower in patients receiving nilotinib compared with imatinib and no patient who achieved a MR4.5 progressed at any time.

In the DASISION trial, transformation to the accelerated or blast phase occurred in fewer dasatinib-treated patients than imatinib-treated patients during the treatment phase (3 % vs. 5 %) and after discontinuation of treatment (4.2 % vs. 6.1 %). Progression-free survival rates at 36 months were 91 % and 90.9 %, respectively, while overall survival rates were 93.7 % and 93.2 % [28].

Taking all the above data together, both the ENESTnd and DASISION trials have demonstrated that, as the response to the second-generation TKI is greater and more rapid than the response to imatinib, patients treated with second-generation drugs have a higher probability of achieving an optimal response to treatment.

3 Differentiating Patient Subgroups to Achieve the Best Outcomes As described above, both available and approved secondgeneration TKIs can produce better therapeutic outcomes than imatinib, so the decision on whether to use dasatinib or nilotinib cannot be judged solely on efficacy. Based on their pharmacodynamic and pharmacokinetic properties, there may be sub-populations of CML patients for whom one treatment is more suitable; therefore, to explore potential factors that can influence treatment outcomes, specific concomitant conditions of patients, as well as exclusion and inclusion criteria in the DASISION and ENESTnd trials were examined.

Exclusion criteria from both studies are reported and compared in Table 1 [18, 19]. Exclusion criteria of the ENESTnd trial appear to be more numerous than the DASISION trial; both exclude patients receiving QT interval medications, CYP3A4 modifiers and prior TKI treatment and have criteria relating to specific gender/ reproductive status. The ENESTnd trial also excluded patients receiving other CYP2C8, CYP2C9, CYP2DD and UGT1A1 substrates, or those who have undergone previous radiotherapy or surgery. Patients were excluded from participation in the initial dasatinib clinical studies if they were using medications that inhibited platelet function or were anticoagulants. In subsequent trials, their use was allowed if the platelet count was [50,000/mL. Some of the most common co-morbidities that could present a challenge during nilotinib or dasatinib treatment (and were included as exclusion criteria in the ENESTnd and/or DASISION trials) are discussed in detail below.

3.1 Hypertension Hypertension is the most common and important risk factor for cardiovascular mortality. It increases the risk of coronary heart disease, stroke, congestive heart failure and

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Table 1 Exclusion criteria and prohibitions for the ENESTnd and DASISION studies [18, 19]

Previous medications

ENESTnd

DASISION

Treatment with TKIs prior to study entry is not allowed, except in the following situation: in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of Gleevec�/Glivec� at any dose may be prescribed to the patient but for no longer than 2 weeks in duration

Any prior treatment with interferon, with dasatinib, with imatinib Any other prior systemic treatments, with anti-CML activity (except for anagrelide or hydroxyurea)

Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide End organ function

Adequate end organ function as defined by:

Adequate end organ function defined as:

1. Total bilirubin \1.5 9 ULN,

Total bilirubin B2.0 9 ULN;

2. SGOT and SGPT \2.5 9 ULN,

ALT and AST B2.5 9 ULN.

3. Creatinine \1.5 9 ULN,

Creatinine B3 times 9 ULN

4. Serum amylase and lipase B1.5 9 ULN, 5. Alkaline phosphatase B2.5 9 ULN unless considered tumor related Cardiac function

Impaired cardiac function including any one of the following: History of clinically documented myocardial infarction

Uncontrolled or significant cardiovascular disease, including any of the following:

History of unstable angina (during the last 12 months)

A myocardial infarction within 6 months

Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled hypertension)

Uncontrolled angina within 3 months

Congenital long QT syndrome or a known family history of long QT syndrome

Diagnosed or suspected congenital long QT syndrome

History of or presence of clinically significant ventricular or atrial tachyarrhythmias.

QTc [450 ms on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF [450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc

Congestive heart failure within 3 months Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) Prolonged QTcF interval [450 ms on pre-entry ECG

LVEF \45 % or below the institutional lower limit of the normal range (whichever is higher) as determined by locally read echocardiogram Inability to determine the QT interval on ECG Complete left bundle branch block Use of a ventricular-paced pacemaker Clinically significant resting bradycardia (\50 beats/min) Concomitant medications

Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon) Patients actively receiving therapy with strong CYP3A4 inhibitors Patients actively receiving therapy with strong CYP3A4 inducers

Prior chemotherapy for peripheral stem cell mobilization.

(Prior collection of unmobilized peripheral blood stem cells is permitted) Subjects currently taking drugs that are generally accepted to have a risk of causing torsades de pointes

Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug Further criteria

Previously documented T315I mutations

Known pleural effusion at baseline

History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease

ALT alanine transaminase CML chronic myeloid leukaemia, CYP cytochrome P450, LVEF left ventricular ejection fraction, TKIs tyrosine kinase inhibitors

Second-Generation TKIs in CML

myocardial infarction [29]. Furthermore, in patients with hypertension, there is a common occurrence of other cardiovascular risk factors such as diabetes mellitus and obesity [30]. In 2000, hypertension was estimated to affect one quarter of the adult global population, or 1 billion people worldwide, with a third to a half of adults in Europe having hypertension [31, 32]. The prevalence of hypertension increases with age, and each decade of life over the age of 30 years is associated with a 10 % increase in prevalence [31, 33].

The European guidelines for the management of hypertension identify thiazide diuretics, angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs), b-blockers (BBs) or calcium channel blockers (CCBs) as the drugs of choice for the treatment of hypertension. However, the potential for metabolic or drug-drug interactions to occur with these treatments and second-generation TKIs should be carefully considered.

The protocol for the ENESTnd trial excluded those with uncontrolled hypertension [19] ([140/90 mmHg for all patients or [130/80 mmHg in patients with type 2 diabetes [30]), while no such restriction was in place for the DASISION study [18].

According to the summary of product characteristics (SmPC) for nilotinib, the potential for the drug to inhibit CYP2C9, CYP2D6 and CYP3A4 enzymes could lead to potential alterations in the pharmacokinetics of ARB, BB and CCB treatments [21]. As such, nilotinib should be coadministered with caution in patients taking a number of the antihypertensive treatments in these classes (Fig. 1) [21]. In contrast, dasatinib, owing to to its effect only on CYP3A4, requires careful attention only for patients who are receiving CCBs [23]. However, caution with dasatinibtreated hypertensive patients is required as they may be more prone to develop a pleural effusion (see Sect. 3.5).

3.2 Diabetes Mellitus It has been estimated that 346 million people have diabetes worldwide (90 % of which is type 2 diabetes) and in Europe approximately 60 million people are affected [34, 35]. Uncontrolled diabetes is associated with long-term complications and a greater risk of mortality [36]. The principal component of the treatment is managing glucose levels in the blood, glycosylated haemoglobin, down to a target level of about the upper limit of normal (6.5 %).

In the ENESTnd trial, patients with uncontrolled diabetes were excluded. Notwithstanding this exclusion, the ENESTnd trial showed that treatment with nilotinib was associated with elevated blood glucose levels: at 18 months, hyperglycaemia was observed twice as frequently in patients treated with nilotinib 300 and 400 mg

compared with patients treated with imatinib (36 % and 41 % vs. 20 %, respectively), but the rates of grade 3 or 4 hyperglycaemia were only 6 % with 300 mg and 4 % with 400 mg nilotinib compared with zero with imatinib [37].

Comparing the rates of discontinuation in the study, 35 % of patients with ‘controlled’ diabetes who received nilotinib 300 mg twice daily discontinued treatment compared with 20 % of the overall population, but no differences were reported in terms of efficacy [37, 38]. The SmPC for nilotinib reflects these results and identifies increased blood glucose amongst the potential risks with this treatment [21].

In contrast to ENESTnd, in the DASISION trial there were no enrolment restrictions on diabetes status: at the 24-month follow-up, there were no reported increases in glucose (mild or severe). Furthermore, the SmPC for dasatinib does not provide any warning regarding treatment effects on glucose [23].

3.3 Cardiovascular Disease Cardiovascular diseases include coronary heart disease, cerebrovascular diseases, peripheral arterial occlusive diseases (PAOD), rheumatic heart disease, congenital heart diseases, deep vein thrombosis and pulmonary embolism.

Elevated blood pressure, elevated blood glucose or lipids, excess body weight and smoking status are the main risk factors recognised worldwide for cardiovascular disease. In terms of the burden of the disease, the WHO lists cardiovascular diseases as the largest cause of death and disability in the world; in 2008, cardiovascular diseases were responsible for the deaths of over 17 million people and this is estimated to be 23.6 million by 2030 [39].

Cardiac adverse events have been noted in 13.2 % of patients receiving nilotinib and, to date, ten cases of sudden cardiac death have been reported for nilotinib [21, 40]. As a result, subsequent studies such as the ENESTnd trial have employed stringent criteria to exclude any patients with a history of cardiac disease (for example, all patients with a previous myocardial infarction). Despite stringent selective criteria to exclude patients with cardiovascular diseases, grade 3–4 adverse events related to ischaemic heart disease in the ENESTnd trial occurred more frequently in both nilotinib arms compared with the imatinib arm at the 36-month follow-up (nilotinib 300 mg twice daily, 3.2 %; nilotinib 400 mg twice daily, 4.0 %; imatinib 1.1 %).

Three patients receiving nilotinib 400 mg twice daily discontinued therapy because of an ischaemic heart disease event. There were no cases of QTc prolongation C500 ms or left ventricular ejection fraction B45 % during nilotinib treatment [25].

Peripheral arterial occlusive diseases can occur in patients treated with TKIs and several reports have focused on whether the incidence of PAOD is increased in patients

E. Abruzzese et al.

Fig. 1 Potential drug-drug interactions that limit the use of (a) nilotinib or (b) dasatinib in patients with hypertension [21, 23]. ACE angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor

blocker, BB b-blocker, CCB calcium channel blocker, SmPC summary of product characteristics, TD thiazide diuretics

treated with nilotinib [41, 42]. A retrospective analysis of three randomized phase III studies in patients with chronicphase CML (IRIS, TOPS and ENESTnd) reported PAOD rates in 2,390 patients divided into three cohorts: imatinib (n = 1301), nilotinib (n = 556) or no TKI (n = 533). This analysis demonstrated that the exposed-adjusted risk of the PAOD ratio was not statistically different between nilotinib and imatinib cohorts when compared with patients who did not receive a TKI [43]. However, the different cardiac inclusion/exclusion criteria, the lower rate of PAOD in

imatinib patients when compared with the CML patients who did not receive a TKI and the low incidence of either nilotinib- or imatinib treated-patients compared with the age-matched nonCML population suggests caution. In all PAOD-reported cases, a strong correlation with wellknown risk factors (hypertension, diabetes, hyperlipidaemia, and smoking) was observed.

Peripheral arterial occlusive diseases and other arterial events have also been described with the newest TKI ponatinib (IclusigTM, ARIAD Pharmaceuticals), which has

Second-Generation TKIs in CML

recently been approved for patients with failure or intolerance to prior TKI therapy. Reports of PAOD and arterial events with ponatinib have warranted a black-box warning for arterial thrombosis on the package insert [44]. This suggests that cardiovascular risk factors (obesity, hypertension, hypercholesterolemia, smoking and diabetes) should be accurately studied and managed before and during TKI treatment.

No sudden deaths have occurred in previous studies with dasatinib and the rate at which the agent induces QTc prolongation is approximately one third that of imatinib. At 24 months, DASISION data showed pulmonary hypertension rate of 1.2 % (three patients: two grade 1, one grade 2), while drug-related cardiovascular adverse events of all WHO grades occurred in 6.6 % of dasatinib recipients, compared with 5.4 % of imatinib recipients. It is worthwhile noting that the selection criteria for DASISION were less restrictive; for example, the study protocol permitted patients with a myocardial infarction occurring more than 6 months before CML diagnosis to be included [28].

However, to reflect the risk observed with other TKIs, the SmPC for dasatinib states that patients at risk of developing prolonged QTc should be carefully monitored [23].

Furthermore, the SmPC for dasatinib mentions that postmarketing reports of dasatinib treatment have also reported incidences of pulmonary hypertension in patients receiving dasatinib [45], particularly in those patients receiving concomitant medications or who have co-morbidities [23].

As such, the SmPC for dasatinib states that patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib therapy and if pulmonary hypertension is confirmed, dasatinib should be permanently discontinued [23].

3.4 Biochemical Abnormalities and Haematological Toxicity Distinct differences also exist between nilotinib and dasatinib for laboratory outcomes, including lipase, amylase, bilirubin and alanine transaminase (ALT) and haematological toxicity.

Three-year ENESTnd data indicated that grade 3/4 increases in lipase levels occurred in 7.5 % and 7.9 % of nilotinib 300 and 400 mg twice-daily recipients, respectively. Increases in bilirubin (grade 3/4 3.9 % and 7.9 %) and ALT (grade 3/4 4.3 % and 9.4 %) were also observed [25]. However, these changes are usually transient, asymptomatic and easily manageable [19]. Conversely, in the DASISION study, no changes in lipase, amylase, ALT, aspartate transaminase (AST) or total bilirubin were observed with dasatinib at 24 months [28].

As a result of these observed effects, warnings are in place in the nilotinib SmPC regarding its use in patients

with a history of pancreatitis, as well as dose-reduction or cessation strategies in the event of bilirubin or hepatic transaminase elevations [21].

The 24-month data indicate that compared with dasatinib treatment, nilotinib was associated with a lower occurrence of grade 3/4 myelosuppression. Using imatinib treatment as the reference point for comparison of the ENESTnd and DASISION trials, in ENESTnd, anaemia, neutropenia and thrombocytopenia occurred less frequently in patients treated with nilotinib than in patients treated with imatinib (4 %, 11–12 % and 10–12 %, for anaemia, neutropenia and thrombocytopenia, respectively, with nilotinib 300/400 mg twice daily and 4 %, 21 % and 9 % with imatinib) [24]. Conversely, in the DASISION study, these adverse events occurred more frequently with dasatinibthan in imatinib-treated patients (11 %, 24 % and 19 %, for anaemia, neutropenia and thrombocytopenia, respectively, with dasatinib and 8 %, 21 % and 11 % with imatinib) [28].

3.5 Chronic Pulmonary Diseases Chronic pulmonary diseases comprise different conditions affecting the lungs and the respiratory system, such as chronic bronchitis, pleural effusions, emphysema and chronic obstructive pulmonary disease: the prevalence of these conditions increases with age [46, 47] and is associated with increases in direct healthcare costs [48].

Pleural effusions are the most common extra-haematological toxicity observed during dasatinib treatment and their occurrence can require dose reduction or discontinuation [49–51]. The aetiology of pleural effusions is unclear; dasatinib-induced inhibition of PDGF receptor or an immune-mediated mechanism may be implicated [52, 53].

In the DASISION study, where patients with concomitant chronic pulmonary diseases were excluded, the 3-year all-grade incidence of pleural effusions was 17.5 % in dasatinib recipients compared with 0.4 % in imatinib recipients [27]. However, pleural effusions were generally manageable with temporary drug interruption and it is worth noting that the occurrence of pleural effusions during dasatinib treatment did not affect the efficacy of the drug in the DASISION study or in any of the other clinical trials previously reported. Porkka et al. [54] showed that the incidence of pleural effusions was significantly reduced with dasatinib 100 mg four times daily compared with dasatinib 50 mg, 70 mg bid or 140 mg QD (14 % vs.

23–26 %, respectively) over a 24-month minimum followup. Similar to the DASISION study, short- and long-term efficacy were similar across all dose regimens and were not affected by occurrence of pleural effusion.

Several patients receiving dasatinib have experienced pleural effusion, an extra-haematological toxicity that may be associated with cardiovascular events and occur at a

E. Abruzzese et al.

greater rate in patients with underlying cardiopulmonary disease prior to initiating dasatinib. Given the association between dasatinib treatment and pleural effusions, and the fact that patients with underlying chronic pulmonary diseases were excluded from clinical trials, the use of dasatinib in these patients should be avoided [23].

3.6 Other Co-morbidities Dasatinib has been shown to induce immune system alterations (e.g. altered T-cell function, expanded lymphocyte subpopulations) indicating that it should be used with caution in patients with concomitant autoimmune diseases or immune-related conditions [55, 56], particularly as treatment with dasatinib can increase the risk of infection [57]. This inhibition of the immune system by dasatinib is via Src and although overexpression of Src plays an important role in the pathogenesis of cancer, the normal expression of Src is necessary to maintain immune responses [58, 59]. In particular, cancer cells (which are weakened by chemotherapy) need to be cleared from the body by immune cells. Thus, immunotherapy has been used to increase the effect of chemotherapy and reduce the dose of cytotoxic drugs and therefore reduce their adverse effects [60].

In the DASISION study, drug-related bleeding events (such as petechiae, epistaxis, gastrointestinal haemorrhage and CNS bleeding) were reported in 13 patients (5 % of patients) [18]. After a minimum follow-up of 13 months, one patient (\1 %) receiving dasatinib had grade 3 haemorrhage and after a minimum of 36 months follow-up, the cumulative rate of grade 3 haemorrhage was 1 % (two patients) [18]. Other clinical studies show that the most bleeding-related events in patients receiving dasatinib were typically associated with grade 3 or 4 thrombocytopenia indicating that it should be used with caution in patients with a history of a serious bleeding disorder unrelated to CML [23], which was an exclusion criterion of the DASISION study [18].

4 Conclusions The advent of targeted therapy for the treatment of CML has greatly improved treatment outcomes for patients. The

first such treatment, the BCR-ABL TKI imatinib, has been used successfully for approximately a decade and has been joined by two second-generation TKIs: dasatinib and nilotinib. While the second-generation TKIs produce more rapid responses than imatinib they have not yet shown any overall survival advantage compared with long-term administration of imatinib. However, they are useful in treating imatinib intolerance or resistance and are becoming established as therapeutic options to provide greater depth of response in patients with CML, especially in highrisk patients. With similar levels of efficacy, the choice of second-generation agent should be guided by the characteristics of the individual patient and the most suitable dosing regimen.

When considering the most applicable treatment option, it is important to appreciate that clinical trials often examine highly selected patient populations, which may hamper the extrapolation of clinical study findings to clinical practice. Indeed, given the high proportion of individuals with hypertension, diabetes, cardiovascular disease or chronic bronchopneumopathies in the general population [29, 34, 39], excluding such individuals from clinical trials does not provide results that are applicable in real-life management or that are applicable to many patients seen in daily clinical practice [24]. Interpreting the clinical data in the context of common co-morbidities and existing conditions is critical in establishing the most appropriate treatment strategy for the individual CML patient.

However, based on the clinical evidence of nilotinib and dasatinib, it is important to evaluate the following to determine the most appropriate second-generation TKI treatment for each patient. It has been determined that because of the potential of drug-drug interactions between antihypertensive treatments and nilotinib, nilotinib is not suitable for patients with uncontrolled hypertension. Nilotinib is also not suitable in patients with diabetes or cardiovascular disease because of elevation of glucose levels and the excess of cardiac adverse events observed (Table 2). Furthermore, for those patients with or at risk of pancreas- or liver-related co-morbidities, the high rates of abnormal liver transaminases and pancreatic enzymes observed following nilotinib treatment preclude it as a potential option. Regarding dasatinib, data have confirmed an association with an increased risk of pleural effusions

Table 2 Summary of patient co-morbidities and the suitability of second-generation tyrosine kinase inhibitors [21, 23] Hypertension

Diabetes mellitus*

Cardiovascular disease

Liver or endocrine conditions

Chronic pulmonary disease

Autoimmune disease

Dasatinib

Suitable

Suitable

Possibly suitable

Suitable

Not suitable

Possibly suitable

Nilotinib

Possibly suitable

Not suitable

Possibly suitable

Not suitable

Suitable

Suitable

* Severe diabetes (glycosylated haemoglobin [7 %, high insulin requirement, organ complications)

Second-Generation TKIs in CML

and, therefore, dasatinib should be avoided in patients with coexisting chronic pulmonary disease. Furthermore, caution is required in patients with autoimmune disease because of the action of dasatinib on the immune system (Table 2). In these situations, alternative TKIs (including imatinib) may be more appropriate and should be used.

Acknowledgments The authors would like to thank Matt Weitz and Mary Hines of in Science Communications, Springer Healthcare for providing medical writing support and Simone Boniface for providing post-submission support for this paper. This support was funded by BMS. The authors’ work and the medical writing assistance were independent of the funders. EA received honorarium for advisory board participation from Bristol-Myers Squibb and Novartis; the editorial work was done independently, Springer Healthcare provided funding support. MB received honoraria from Bristol-Myers Squibb, Celgene and Novartis. RL received funding from Bristol-Myers Squibb, Celgene, Novartis and Shire.

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