Update on emerging treatments for chronic myeloid leukemia.

Review

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by McMaster University on 04/01/15 For personal use only.

Update on emerging treatments for chronic myeloid leukemia Carmen Fava†, Alessandro Morotti, Irene Dogliotti, Giuseppe Saglio & Giovanna Rege-Cambrin

1.

Background

2.

Medical need

3.

Existing treatment

4.

Market review

5.

Current research goal

6.

Scientific rationale

7.

Competitive environment

8.

Potential development issues

9.

Conclusion

10.

Expert opinion

University of Turin, San Luigi Hospital, Department of Clinical and Biological Sciences, Orbassano, Italy

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 secondand 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. Keywords: bosutinib, chronic myeloid leukemia, dasatinib, nilotinib, ponatinib, target therapy, tyrosine kinase inhibitors Expert Opin. Emerging Drugs [Early Online]

1.

Background

Chronic myeloid leukemia (CML) is caused by a reciprocal translocation between chromosomes 9 and 22, which produces a fusion gene, BCR-ABL, and a 210 kDa ABL protein (p210) with a constitutive tyrosine kinase (TK) activity. The BCR-ABL product is capable of dysregulating several intracellular pathways in hematopoietic stem cells and myeloid progenitors, and its expression leads to abnormal proliferation, loss of adhesion, inhibition of apoptosis and abnormal DNA repair [1,2]. Clinically, CML is characterized by the expansion and abnormal proliferation of myeloid progenitors, leading to leukocytosis, immature myeloid cells circulating in the peripheral blood, thrombocytosis and splenomegaly. If untreated, the chronic phase (CP) of the disease, characterized by conserved myeloid maturation is followed by the accelerated phase (AP) and blast crisis (BC), characterized by block of terminal maturation. The BC responds very poorly to any treatment and at this stage prognosis remains very poor. Radiation exposure is the best-established risk factor for CML, as demonstrated by Nagasaki and Hiroshima survivors [3]. Epidemiologic data from Europe and USA indicate that CML incidence rate varies from 0.6 to 2.0 per

10.1517/14728214.2015.1031217 © 2015 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

1


C. Fava et al.

100,000 inhabitants/year, with a male to female ratio of 1.3 -- 1.8 [4]. A large population study in the UK indicates that the median age at diagnosis is 59 years [5]. This review will focus on the treatment of CML in CP. Bone marrow transplantation was the first successful treatment in CML starting from the 1980s; later, a-IFN proved to be capable of inducing a cytogenetic remission in around 15 -- 30% of patients with a clear survival advantage in responding patients [6]. This finding was the basis for considering the complete cytogenetic remission (CCyR) a surrogate marker for survival, as later confirmed in further studies [7-9]. In the last 15 years, the discovery of drugs capable to block the BCR-ABL protein activity, the so-called TK inhibitors (TKIs), has opened the way to an oncogene-directed ‘target therapy’, causing a major improvement in CML prognosis, both in terms of disease remission and overall survival (OS). 2.

Medical need

A good management of CML patients requires a careful follow-up, which is based on clinical monitoring as well as on cytogenetic and molecular analysis [10]. Since the first large trial with imatinib, the International Randomized Study of IFN and STI571 (IRIS) trial, it was apparent that obtaining a 3 log-reduction from the BCR-ABL transcript at baseline, as measured by quantitative polymerase chain reaction (RQ-PCR), was associated with good long-term outcome in terms of progression-free survival (PFS): this value was set as Major Molecular Remission (MMR = BCR-ABL ratio £ 0.1%) [11]. Continuing to use TKIs, it has become evident that a further decrease in BCR-ABL can be obtained, with transcript becoming in many cases undetectable, gaining the so-called complete molecular remission (CMR). With the aim of improving the accuracy and the reliability of the quantitative analysis, this definition has evolved into MR (molecular remission) 4, MR4.5 or MR5, corresponding to 4, 4.5 or 5 transcript log reduction, respectively (or BCR-ABL/ABL ratio £ 0.01, £ 0.0032, £ 0.001%) based on the control gene level [12]. In the meantime, the technique of RQ-PCR has been standardized [12], allowing the comparison of results from different countries and laboratories. Treatment of CML aims to obtain time-specific end points, as established by international guidelines [10,13]; patients failing these end points remain a clinical challenge. As more TKIs are now available, much attention has been paid to the identification of early prognostic markers during treatment. A strong predictive value has been observed for early molecular response, with BCR-ABL ratio £ 10% at 3 months, and BCR-ABL ratio £ 1% at 6 months being predictive for OS and PFS [14]. Recently, the velocity of BCR-ABL transcript elimination has also been shown to represent an additional prognostic index; among patients with BCR-ABL > 10% at 3 months, the prognosis is poorer for patients with a BCR-ABL halving time of > 76 days [15]; patients with less than half-log reduction in BCR-ABL 2

transcript at 3 months are more at risk of disease progression [16]. These time-points are therefore key ‘decision points’ to be used for evaluating a treatment change in patients who do not respond well to a first-line inhibitor. According to the National Comprehensive Cancer Network guidelines [13], a shift in treatment is recommended in patients with a transcript > 10% at 3 months, whereas European Leukemia Net recommend to change therapy if BCR-ABL is over 10% at 6 months [10]. If early response is a good predictor of OS and PFS, it also predicts the earlier achievement of a deep molecular response, which is required for a safe discontinuation of therapy [17]. The psychological and economical burden of a lifelong treatment is very high, and quality of life (QoL) can be reduced especially in young patients. Furthermore, the use of TKI during pregnancy remains contraindicated, as data on a limited number of imatinib use in pregnant women suggested a possible increase in neonatal defects compared to the normal population [18]. A number of clinical trials investigating the possible discontinuation of treatment are ongoing and try to answer these issues: the overall rate of relapse-free survival ranges between 40 and 60% depending on criteria for discontinuation and for restarting the drug [17]. A stable deep molecular response is a well-established criterion for discontinuation, meaning that a MR4 or MR4.5 (rarely MR5) for at least 1 or 2 years is required. However, at the moment, < 15% of the patients treated with first-line imatinib can achieve this goal [19]. Strategies to increase the achievement of earlier and deeper response are needed. 3.

Existing treatment

At this moment, three different TKIs (imatinib, nilotinib and dasatinib) are approved for first-line treatment of CML, and two more drugs (bosutinib and ponatinib) are available for resistant/intolerant patients. A drug with a different mechanism of action (omacetaxine) has also been recently approved. a-IFN, the first agent which proved to be able to induce cytogenetic remission in CML patients, is still used in specific settings. Radotinib is a TKI approved in South Korea for second-line CML treatment. Imatinib Imatinib mesylate (Gleevec, Novartis Pharma) is the first TKI which entered the market in 2002 and still is the reference therapy for testing new drugs. Imatinib inhibits ABL, c-Kit, platelet derived growth factor receptor (PDGFR) and NQO2 [20]. After proving its efficacy in late chronic, accelerated and blast phase [21], imatinib 400 mg q.d. was tested in a 1:1 randomized study against IFN + low-dose cytosine arabinoside (IRIS trial). More than 550 patients entered each arm and results for the imatinib group were extremely good, with a cumulative rate of CCyR of 87% at 5 years [22]; after 8 years OS was 85%, with 93% estimated survival if non-CML or transplant-related deaths were excluded; survival without 3.1

Expert Opin. Emerging Drugs (2015) 20(2)


Update on emerging treatments for chronic myeloid leukaemia

progression was 92% [23]. Overall, 45% of the patients discontinued the treatment; the reason was intolerance in 6%, resistance in 17%, transplant in 3% and death in 3% and different miscellaneous reasons in the remaining cases [23]. In another study, 204 CP patients were treated frontline in the years 2000 -- 2006; 25% discontinued the treatment for unsatisfactory response or toxicity, and the probability of remaining at least in Partial Cytogenetic Remission under imatinib treatment at 5 years was 62.7% [24]. Several attempts to improve the results of standard 400 mg daily imatinib dosage, including higher dosage of 600 mg q.d. or 400 mg twice daily (b.i.d.) dosage and different schedules of association with IFN or pegylated-IFN, yielded conflicting results in terms of improvement in molecular response at 12 months, observed in some [25-27], but not in others [28,29]. A significant advantage in PFS and OS, however, was not reported in these studies. A recent report indicates that dose adaption to avoid toxicity results in a dosage of 600 mg daily in most patients and allows obtaining a trend versus a better PFS and OS [27]. Interestingly, young patients seem to profit less from higher imatinib dosage than older ones [30]. Generally, an increase in toxicity with related need for dose reduction is considered the main reason of non-superiority. High body mass may also interfere with response to standard dose imatinib [31]. At standard dosage, all grade main side effects of imatinib are superficial and periorbital edema, nausea, muscle cramps, musculoskeletal pain, rash, fatigue and diarrhea [32]; neutropenia (14.3%), thrombocytopenia (7.8%) and elevated liver enzymes (5.1%) are the most common grade 3/4 laboratory abnormalities [32]. When the QoL has been analyzed, young patients referred a reduced QoL versus healthy age-matched controls, whereas patients over 60 years had a QoL similar to controls. The most common patient referred cause of complaint was fatigue, followed by muscle cramps, musculoskeletal pain and edema [33,34]. Imatinib can be well tolerated in patients over 70 -- 75 years old [35]; in this age group, dose reduction and treatment discontinuation are more frequent in patients with comorbidities, as evaluated by the Charlson Comorbidities Index [36]. Resistance to imatinib may occur as the result of a variety of mechanisms, including variable bioavailability of the drug in the plasma, inadequate intracellular level of the drug, low adherence to treatment, clonal evolution and activation of alternative oncogenic pathways, persistence of Ph+ stem cells and mutations in the BCR-ABL kinase domain, which prevent the binding of imatinib [37]. More than 100 different point mutations have been identified, but 85% of the mutations involves seven amino acid substitutions (M244V, G250E, Y253F/H, E255K/V, T315I, M351T and F359V) [38]. Nilotinib and dasatinib have been first tested as second-line treatment in patients with resistance or intolerance to imatinib and proved to induce a CCyR in around half of these patients. Most mutations arising during imatinib treatment

are sensitive to nilotinib or dasatinb or both, with the relevant exception of T315I. Nilotinib Nilotinib (Tasigna, Novartis Pharma) is molecularly similar to imatinib and has been designed in order to improve the link with the ATP-binding pocket of ABL. Its potency in inhibiting BCR-ABL is roughly 30-fold superior and most imatinib-resistant mutations are sensitive to this drug; apart the aforementioned T315I, a higher IC50 is reported for E255K/V, Y253F/H and F359V/C/I [10,37]. The spectrum of proteins blocked by nilotinib is similar to imatinib and includes c-KIT, PDGFR, NQO2 and DDR1/2 [20]. Nilotinib was first tested in second-line treatment of CML, all phases, in the CAMN2101 trial. Patients were included if they were resistant to imatinib at a dosage of 600 mg, or if a resistant mutation was found in patients treated with the standard 400 mg dosage; in the case of intolerance, they were allowed to enter only in the case of lack of Major Cytogenetic Response (MCyR). Dosage of nilotinib was 400 mg b.i.d. At 24 months, among 321 CP patients, nilotinib induced a MCyR in 59% and CCyR in 44% of the cases; PFS was 64% and estimated OS was 87% [39]. Biochemical abnormalities were frequent and included lipase elevation, hypophosphatemia, hyperglycemia, bilirubin increase and liver enzymes elevation, but rarely caused discontinuation. Rash, pruritus, nausea, fatigue and headache were the most common adverse events. Thrombocytopenia and neutropenia grade 3/4 occurred in 30 and 31% of the patients, respectively [39]. One hundred and thirty-seven patients in AP were also reported: 55% obtained a confirmed hematologic response, whereas a MCyR was obtained in 32 and CCyR in 21% of the patients. Patients with mutations had poorer responses. Estimated PFS and OS at 24 months were 33 and 70% [40]. This trial led to approval of nilotinib as second-line treatment for CML chronic and AP in 2007. Subsequently, two different dosages of nilotinib, 300 and 400 mg b.i.d, were tested versus imatinib 400 mg daily as first-line treatment of CML in the ENESTnd trial, which enrolled around 280 patients for each arm, leading to approval of nilotinib in the first-line setting in 2010. Patients with severe cardiac problems were excluded from the trial. Major end point was MMR at 12 months. MR4 and MR4.5 were also evaluated. At 12 months, a significant increase in MMR was observed in both nilotinib arms (44%, nilotinib 300 mg b.i.d.; 43% nilotinib 400 mg b.i.d.) versus the imatinib arm (22%) [41]. This advantage was confirmed in the follow-up, and persists at 5 years (cumulative MMR 77% both nilotinib arms, 60% imatinib arm) [42]. CCyRs were also superior in nilotinib-treated patients (at 12 months, 80 and 78% with nilotinib 300 and 400 mg b.i.d., respectively, 65% with imatinib); a significant lower number of progression was observed with nilotinib: 2 and 1 in the two nilotinib arms, 11 on imatinib [41]. At 5 years, including all patients on study, progressions occurred in 3.2


3


C. Fava et al.

10 and 6 in nilotinib and 20 patients in imatinib; estimated 5-year survival was 93.6, 96 and 91.6%, respectively. Deep responses (both MR4 and MR4,5) and early molecular end points (BCR-ABL £ 10% at 3 months) were more frequent among nilotinib-treated patients [42]. Mutations appeared less frequently under nilotinib treatment (11 patients in each arm at 3 years) versus imatinib (21 cases) and were associated with progression in 1, 2 and 7 cases respectively. Not surprisingly, the T315I incidence was similar in the three arms, and the difference was due to emergency of imatinib-resistant, nilotinib-sensitive mutations [43]. Patients with treatment failure and suboptimal response enrolled in the ENESTnd trial in nilotinib 300 or imatinib were allowed to enter in a separate extension study switching to nilotinib 400 mg b.i.d. Thirty-five patients were previously treated with imatinib: 26 were not in CCyR (obtained in 58%) and 34 were not in MMR (obtained in 32%). Nineteen patients switched to higher nilotinib dose: 6 were not in CCyR (obtained in 33%) and 18 were not in MMR (obtained in 39%). Interestingly, the progression rate remained higher in patients previously treated with imatinib, with a freedom from progression of 85 versus 95% at 18 months [44]. Around 200 patients with CCyR, but with detectable molecular disease after long-term imatinib therapy were randomized either to continue imatinib or to switch to nilotinib 400 mg b.i.d. (ENEST-cmr study). A significant difference in obtaining a confirmed undetectable transcript was obtained after 2 years (22.1% in nilotinib, 8.7% on imatinib, p = 0.0087). In keeping with the fact that all patients had a good tolerance to imatinib, adverse events leading to drug discontinuation were more common in the nilotinib arm (14 patients vs 3 on imatinib) [45]. Although generally very well tolerated, an increased risk of cardiovascular occlusive events has been reported in patients under nilotinib treatment; generally, these events occur in patients with cardiovascular risk factors [46]. The mechanism underlying is at present unknown; however, a metabolic effect has been hypothesized. In a series of 27 patients from a single center, the level of total, low- (LDL) and high-density lipoprotein cholesterol increased within 3 months of nilotinib treatment, thus increasing the percentage of patients with non-optimal LDL cholesterol level from 48.1 to 88.9% [47]. Nilotinib has also been shown to induce hyperglycemia, possibly via insulin resistance, in a proportion of patients [41,48]. Recent studies indicate that assessment for cardiovascular risk factors (biochemical metabolic markers, ankle-brackial index) may be of great value in the early identification of vascular pathology, thus allowing the proper treatment of predisposing conditions [46]. Dasatinib Dasatinib (Sprycel, Bristol-Myers-Squibb) is a potent dual SRC/ABL inhibitor with activity on a wide number of kinases. Unlike imatinib and nilotinib, it reacts with the 3.3

4

BCR-ABL protein in its activated form. It also differs from the other two drugs for its short extracellular half-life. It is active against most ABL mutations, with the exception of T315I/A, F317L/V/I/C and V299L [10,37]. The activity of dasatinib in resistant and intolerant CML patients, all phases, has been shown by different studies and led to the approval of the drug for all phases of CML and Ph+ acute lymphoblastic leukemia (Ph+ ALL) in 2006. The dosage at start was 70 mg b.i.d., but a dose adaptation experiment (034) showed that a single dosage of 100 mg daily was as effective and less toxic than the other tested dosages (50 and 70 mg b.i.d., 140 mg q.d.) [49]. In CP patients, 100 mg q.d. dasatinib treatment led to 50% CCyR by 24 months [49]. At the 6-year follow-up of the same group of patients, PFS was 49%, OS (on intention to treat [ITT] basis) was 71%, and cumulative MMR was 43%; 31% of the patients remained on treatment; the cause of study discontinuation was toxicity in 21% and progression in 21% [50]. Adverse events occurring in > 40% of the patients, all grades, were musculoskeletal pain, headache, infection and diarrhea. Grade 3/4 main toxicities were infection (6%) and pleural effusion (PE) (5%). The overall incidence of PE was 25.3%, and it was the cause of discontinuation in 6.7% of patients [50]. In the DASISION study, 516 treatment-naive CP CML patients received first-line treatment either with dasatinib 100 mg q.d. or with imatinib 400 mg q.d. in a 1:1 random, stratified by Hasford risk score. Major end point was confirmed CCyR by 12 months, and this was significantly better in the dasatinib arm (77 vs 66%, p = 0.007), allowing the approval of the drug as first-line treatment of CP CML in 2010. The cumulative MMR rate was 64 versus 46% by 24 months, with a median time to MMR of 15 versus 36 months; progression to AP/BC was observed in 6 versus 13 patients, respectively [51]. A better trend for MR4 and MR4.5 was present in the dasatinib arm, and it has been confirmed at the 4-year follow-up; 84% with respect to 64% patients had BCR-ABL £ 10% at 3 months; OS remains very good in both arms (92.9 vs 92.1%, ITT). Rate of newly occurring mutations was similar (17 vs 18 cases) [52]. Another random 1:1 study compared dasatinib 100 mg to imatinib 400 mg and included 256 CP-CML patients. Results were evaluated at 12 months; rate of CCyR, MMR, MR4 and MR4.5 were all better in the dasatinib arm, whereas PFS and OS were similar [53]. In the DASISION study, adverse events caused 14% rate of dasatinib discontinuation; PE, any grade, was observed in 22% of the dasatinib-treated patients [50]. Risk factors for PE include advanced age, comorbidities, hypertension, cardiac disease, autoimmune disorders, twice daily and higher dasatinib dosage, high cholesterol and lymphocytosis [54]. Tolerability of dasatinib was otherwise generally good and very few laboratory anomalies other than hematologic toxicity have been reported. Neutropenia and thrombocytopenia grade 3/4 have been observed, respectively, in 25 and 20% of naive patients with a 4-year follow-up (DASISION study) [52],




and in 36.4 and 23.6% of late CP treated with dasatinib 100 mg q.d at the 6 years update [50]. Bleeding has been reported mainly in association with thrombocytopenia and advanced phase CML, but a platelet dysfunction has also been observed [55]. An immunomodulatory effect has been reported for dasatinib, associated with lymphocytosis and clonal expansion of large granular lymphocytes (natural killer or T lymphocytes); this effect seems to be more frequent in patients with PE; a positive correlation with clinical response has also been reported in several series [54]. Pulmonary arterial hypertension (PAH) is a rare but clinically relevant adverse events presenting mainly as exertion dyspnea and diagnosed on the basis of right heart catheterization; brain natriuretic peptide elevation is also observed in most patients, and aspecific signs of PAH can be observed at standard cardiac Doppler ultrasonography [56]. Bosutinib Bosutinib (Bosulif, Pfizer) is an orally bioavailable, potent dual SRC/ABL inhibitor, 200 times more active than imatinib against imatinib-resistant mutants of BCR-ABL, except T315I. It inhibits BCR-ABL signaling in CML cells, with a minimal inhibition of c-kit and PDGFR. Bosutinib was initially tested in a dose-escalation Phase I study on cohorts of patients with CP imatinib-resistant CML. The dose of 500 mg q.d. was selected for the Phase II study, including 288 patients documented as having imatinib-resistant (2/3 of the patients) or intolerant disease [57]. The primary end point was MCyR at 6 months, and this was achieved in 31% of the patients treated. At any point during a median follow-up of 24 months, 53% of evaluable patients achieved a MCyR and 41% achieved a CCyR. Among patients who achieved a CCyR and were evaluable for molecular response, 64% of imatinib-resistant and 65% of imatinib-intolerant patients achieved a MMR; 49 and 61% achieved a CMR, respectively. Bosutinib was also effective when used as third/fourth-line therapy (Table 1) [58]. On the basis of these results, bosutinib was approved for treatment of CML patients, all phases, with resistance or intolerance to prior therapy in 2012. Bosutinib was also compared to imatinib in terms of efficacy and safety in a Phase III trial [59], which enrolled patients with untreated CML in CP. Bosutinib did not show superiority in the achievement of CCyR at 12 months which was the primary end point, although the MMR and CMR rates at 12 months were significantly higher with bosutinib than with imatinib. The reason was probably the unexpectedly high number of patients who discontinued bosutinib treatment before the first efficacy assessment. Among patients, including second-line CP CML, third-/ fourth-line CP CML, and advanced leukemia, the most common toxicities reported were gastrointestinal (diarrhea, nausea and vomiting). Diarrhea presented early, with 8% of patients experiencing grade 3/4 events. Grade 3/4 myelosuppression 3.4

was reported in less than half of patients. Alanine aminotransferase (ALT) elevation occurred in 17% of patients but rechallenge post-interruption was successful in most of the patients [60]. Ponatinib Ponatinib (Iclusig, Ariad) is considered a third-generation TKI, as it is the first compound in the class of TKIs to exhibit activity against CML presenting the T315I mutation. Beside BCR-ABL, it also targets other therapeutically relevant kinases such as FLT3, FGFR, VEGFR and PDGFR, and c-KIT. It is considered 500 times more potent than imatinib, and it contains a novel triple-bond linkage that avoids the steric hindrance caused by the bulky isoleucine residue at position 315 in the T315I mutant [61]. Among the BCR-ABL mutants tested, the E255V mutant, which confers high-level resistance to imatinib and intermediate-level resistance to and dasatinib, was the most resistant to ponatinib, whereas ponatinib potently inhibited mutants at residues Y253 and F359 (resistant to nilotinib) as well as F317 (resistant to dasatinib). At doses ‡ 30 mg, in vivo trough blood ponatinib level surpassed the 40 nM concentration that was found to completely inhibit the emergence of any BCR-ABL mutations in preclinical studies [61]. Among 43 patients with late chronic-phase CML, enrolled in the Phase I study, 72% had a MCyR and 63% a CCyR [62]. On the evidence of these results and on the safety profile, patients were enrolled in the Phase II PACE trial and received an initial dose of 45 mg of ponatinib once daily orally [63]. Two hundred and sixty-seven patients received ponatinib in CP: 56% achieved a MCyR by 12 months, 51% of patients with resistance or intolerance to dasatinib or nilotinib and 70% of patients with the T315I mutation. Fifty-three per cent of patients maintained or achieved a BCR-ABL transcript level £ 10% by 3 months, with a trend towards higher rates in patients receiving fewer prior approved TKIs. The MMR rate improved over time, being 28% by 9 months. With a followup of 2 years, the rates of MCyR and CCyR were even higher (Table 2) [64]. The PACE trial supported the approval of ponatinib for CP, AP or BP CML or Ph+ ALL patients who are resistant or intolerant to prior TKIs in December 2012. On the basis of the excellent results of the PACE study, ponatinib was tested front-line in a randomized study, compared with imatinib standard dose. The median follow-up was 3 months, due to early discontinuation of the study. The rates of MMR were 29, 66, 83% at 3, 6 and 9 months, respectively, on the evaluable patients [65]. Common adverse events with ponatinib were thrombocytopenia, rash, dry skin and abdominal pain. Other notable toxicities in the PACE study included arterial thrombotic events and pancreatitis. With a median follow-up of 24 months, all grade treatment-related cardiovascular events, including arterial thromboembolic events, venous thromboembolic events and cardiac failure were 31%; grade 3 -- 4 events were 19% [66]. For hematologic and non-hematologic adverse events, 3.5


5

C. Fava et al.

Table 1. Efficacy of bosutinib in CP-CML patients treated with $ 2 TKIs [58].


Bosutinib, patients in CP Total population (n) Imatinib + dasatinib resistant Imatinib + dasatinib intolerant Imatinib + nilotinib resistant Imatinib + dasatinib + nilotinib Rate of responses (%) Major cytogenetic response Complete cytogenetic remission Major molecular remission Complete molecular remission

118 37 50 27 4 32 24 15 11

CML: Chronic myeloid leukemia; CP: Chronic phase; TKI: Tyrosine kinase inhibitor.

Table 2. Efficacy of ponatinib in CP-CML patients treated with $ 2 TKIs, or with the T315I mutation [64]. Ponatinib, patients in CP Total population (n) One previous approved TKI Two previous approved TKI Three previous approved TKI Four previous approved TKI Rate of responses (%) Major cytogenetic response Complete cytogenetic remission Major MR MR4 MR4.5

270 19 98 141 12 58 52 36 22 15

CML: Chronic myeloid leukemia; CP: Chronic phase; MR: Molecular remission; TKI: Tyrosine kinase inhibitor.

multivariate analyses showed that dose intensity is the most significant predictor of adverse events. In November 2013, the increasing rate of vascular thrombotic events led to a temporary suspension of ponatinib sale in the US, as well as the modification or closure of several clinical trials, including the randomized trial with imatinib or ponatinib in front-line patients. The European Medicines Agency’s Committee for Medicinal Products for Human Use recommended measures to reduce risk. Clinicians were encouraged to start the treatment with 45 mg/day and reduce to 15 mg/day after the achievement of MCyR, with re-escalation to 30 or 45 mg/day if response was lost, provided there were no serious adverse events. The impact of dose modification on response was assessed by grouping patients according to tertiles of cumulative dose divided by treatment exposure. Comparable response rates were seen between patients with average dose intensity > 27 to £ 42 and > 42 mg/day. Response rates were lower in patients with average dose intensity £ 27 mg/day; 6

however, these patients still achieved MCyR, CCyR and MMR rates that substantially exceeded those reported with the most recent dasatinib- or nilotinib-containing regimen [66]. Since December 2013, ponatinib is approved for CP, AP, or BP CML or Ph+ ALL patients for whom no other TKI therapy is indicated or with the T315I mutation. Radotinib Radotinib (Supect, YL-Yang Pharm, South Korea) is a second-generation TKI, active on wild-type and mutated BCR-ABL with the exception of T315I. A Phase II trial included 77 resistant and intolerant CML patients in South Korea; by 12 months, MCyR was obtained in 75% and CCyR in 47%; discontinuation rate during the first 12 months was 42.9%, mainly due to biochemical abnormalities (19.5%) including grade 3/4 thrombocytopenia, hyperbilirubinemia, hyperglycemia, ALT and lipase elevation. Estimated OS and PFS at 12 months were 96.1 and 86.3%, respectively. Radotinib has been approved for treatment of CML intolerant or non-responsive to other treatment in South Korea in January 2012 [67]. 3.6

a-IFN As a single agent, IFN treatment has been replaced by the less toxic and more effective TKIs. However, the immunologic effect of IFN as well as its possible direct effect on CML stem cells may still be relevant on leukemic patients [68]. Four large randomized trials investigated the use of IFN, either standard or pegylated, in association with imatinib, with discordant results. An advantage in MMR was reported in two studies [26,69] and not observed in the other two [25,70]; rate of CCyR, OS and PFS did not differ. A previous therapy with IFN has been reported to increase the rate of treatment-free survival after imatinib discontinuation [17]. Although the role of IFN has been hampered by its high impact on QoL, its use has contributed to indicate that immunity may play a clinically relevant anti-leukemic role in CML even in the TKIs’ era [68]. 3.7

Omacetaxine mepesuccinate Omacetaxine mepesuccinate (Synribo, Teva) is a protein synthesis inhibitor and is prepared by a semisynthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. It is able to induce apoptosis in leukemic cells by reducing levels of multiple oncoproteins, including BCR-ABL [71]. In vitro studies show that omacetaxine can also induce apoptosis of leukemic stem cells (LSC) [71]. It has shown promising activity in CML patients with resistance or intolerance to TKI therapy, including patients with a T315I BCR-ABL mutation. Recently, a multi-centre Phase II trial (CML-203) evaluated the efficacy of omacetaxine mepesuccinate in patients with CML-CP and CML-AP who had failed two or more prior TKIs [72]. MCyR and major hematologic response were the primary end points for CML-CP and CML-AP, respectively. Forty-six CP patients were enrolled; MCyR 3.8




were reported in 10 patients (22%); the median OS was 30.1 months and PFS was 7 months. In a Phase II, openlabel, multi-centre trial of subcutaneous (s.c.) omacetaxine in patients with CML who had failed prior TKI therapy and harbored the T315I mutation (CML-202), 62 patients were treated with omacetaxine [73]. Fourteen patients achieved MCyR (23%). Grade 3/4 hematologic toxicity included thrombocytopenia, neutropenia and anemia. Nonhematologic toxicities were mainly grade 1/2 and included diarrhea, nausea, fatigue, pyrexia, headache and asthenia. On the basis of the results of patients in study CML-202 and CML-203 [74], omacetaxine was approved in US in 2012 for the treatment of CML in adults in the CP or AP of the disease after failure (resistance and/or intolerance) of prior therapy with ‡ 2 TKIs. It is administered on a dose of 1.25 mg/m2 s.c. b.i.d. for 14 consecutive days of a 28-day treatment cycle, then followed by a maintenance regimen of 1.25 mg/m2 b.i.d. for 7 consecutive days per cycle once hematologic response is achieved. 4.

Market review

As survival of patients has dramatically increased over time, the prevalence of the disease is steadily increasing: the median expected lifetime in a newly diagnosed patient has been estimated to be 22 years, and prevalence is expected to exceed about 35 -- 40 times the incidence when the plateau will be reached, which is believed to occur around year 2050 [75]. This means a population of CML patients of ~ 181,000 in the USA. Both clinical trials [22] and population-based studies [5] have confirmed the improvement in survival of CML patients; however, data from Europe [5] and from the USA [76] are somewhat diverging, suggesting that the potentially more widespread access to TKIs in European Countries may play a role in this differences; survival may also be influenced by other socioeconomical factors, such as the healthcare setting, that is treatment in teaching hospital versus officebased physicians [77], and by living in more deprived areas [5]. The financial burden for treatment is high, but the real economic impact is still a matter of debate [5,78]. TKI treatment is costly but it is considered cost-effective in many studies. The perspective of treatment discontinuation is attractive both for patient safety and QoL and for economical reason. 5.

Current research goal

In spite of the outstanding progress in this field of oncology, a number of open questions remain to be solved. The treatment of advanced phases is still unsatisfactory, and allogeneic stem cell transplant is still recommended in fit patients [10,13]. Although the use of second-generation TKIs nilotinib and dasatinib has increased the proportion of patients capable of obtaining an optimal response, the treatment of resistant and suboptimally responding patients is still debated and the

role of third-generation TKIs remains to be completely defined. A number of safety issue have been raised for long-term use of TKIs, which may become more relevant as patients get older, as most side effects are associated with concomitant morbidities, including metabolic, cardiovascular and pulmonary chronic diseases. 6.

Scientific rationale

For many years, resistance to TKIs was commonly ascribed to BCR-ABL mutations preventing TKIs to inhibit the kinase activity of ABL. Other mechanisms of resistance are BCRABL amplification or overexpression, clonal evolution and decreased cell exposure to drugs. More recently, it was demonstrated that LSC survival and maintenance is not affected by TKIs, suggesting that additional cellular mechanisms may be involved in the development of CML resistance. Among these Pro-mylecytic Leukemia (PML) was shown to control Ph+ LSC maintenance [79]. Other genes, that play a role in the response to oxidative stress, in inflammation and cancer, like Arachidonate 5-lipoxygenase (5-LO) gene (Alox5), have been reported to exert a critical regulatory effect on CML stem cells [80]. On this basis, Arsenic trioxide (ATO) (PML inhibitor) and Zileuton (Alox5 inhibitor) are currently tested in clinical trials on resistant patients [81]. BCR-ABL is known to activate a complex network of pathways that promotes survival and proliferation. There are new drugs that may affect several downstream pathways of BCR-ABL, including the RAF/MEK/ERK, the PI3K/AKT/mammalian target of rapamycin (mTOR), and JAK/STAT signaling cascades [81,82]. MEK inhibitors, mTOR inhibitors and JAK2 inhibitors may be good options to overcome resistance. The role of immune system has long been implicated in the control of cancer; it is thought that an immunological activation may help to control the disease, as was demonstrated by the activity of graft-versus leukemia observed after allogeneic bone marrow transplantation. New drugs like nivolumab are expected to reactivate the immune response against CML [83]. 7.

Competitive environment

The expression of BCR-ABL promotes the activation of several signaling transduction pathways that mediate cellular proliferation and survival. Over the years, this complex network of pathways has been dissected and studied in the search of potential additional drugs able to achieve synergistic lethality together with TKIs. In this section of the review, we will report on clinical trials designed to study the most compelling signaling transduction inhibitors in CML. Table 3 lists the compounds which are currently under evaluation in active clinical trials, either alone or in combination with approved TKIs. A number of other drugs have been tested in clinical trials already closed, although results are not yet available [81]. At the moment, in spite of a large


7

C. Fava et al.

Table 3. Open trials testing new drugs for the treatment of CML.


Drug

Target

Association Recruiting

Trials open

NTC

Phase of disease

RAD001

Mammalian target of Imatinib rapamycin inhibitor

Not yet

Phase I/II

BL-8040 Ruxolitinib Nivolumab

Anti-CXCR4 Jak2 inhibitor Anti-PD-1 Ab

Imatinib Nilotinib Dasatinib

Not yet Not yet Recruiting

Phase I/II Phase I/II Phase I

NCT01188889 CP-CML with persistent molecular disease NCT02115672 CP-CML suboptimal NCT01914484 CML/Ph+ ALL NCT02011945 CP/AP-CML

Zileuton

5-lipoxygenase inhibitor PML

Dasatinib

Recruiting

Phase I

NCT02047149 CML resistant

Ima/nilo/dasa Recruiting

Phase I

Jak2 inhibitor

Ima/nilo/dasa Recruiting

Phase I/II

MEK-162

MEK inhibitor

Nilotinib

Not yet

Phase I/II

KB004

Anti-EphA3 Monoclonal Ab Demethylation

Single

Recruiting

Phase I/II

Dasatinib

Recruiting

Phase I/II

NCT01397734 CML resistant/ suboptimal NCT01751425 CML resistant/ suboptimal NCT02225574 advanced CML, Ph+ ALL NCT01211691 AML/ALL/CML/CLL/ MDS/MPN/MM/MF NCT01498445 AP/BC CML

TG-02 cytrate Jak2 inhibitor

Single

Recruiting

Phase I

NCT01204164 BC CML

Tipifarnib

Single

Active not recruiting Active not recruiting

Phase I/II

NCT02210858 CP/AP-CML

Phase I/II

NCT01460498 MRD-CML

Active not recruiting

Phase II

NCT01357655 MRD-CML

Arsenic trioxide Ruxolitinib

Decitabine

Azacitidine

Farnesyltransferase Inhibitor Demethylation

BMS833923

SMO inhibitor

Tyrosine kinase inhibitors Dasatinib

Company

Novartis

Biolinerx Novartis Bristol-Myers Squibb Bristol-Myers Squibb Cephalon Novartis Novartis KaloBios Pharmaceuticals Astex Pharmaceuticals Tragara Pharmaceuticals, Inc. Johnson & Johnson Celgene Corp.

Bristol-Myers Squibb

Source [108]. ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; AP: Accelerated phase; BC: Blast crisis; CLL: Chronic lymphocytic leukemia; CML: Chronic myeloid leukemia; CP: Chronic phase; MDS: Myelodysplasia; MPN: Myeloproliferative neoplasms; MM: Multiple myeloma; MF: Myelofibrosis; MRD: Minimal residual disease.

number of trials, none resulted in the approval of drugs to be used in combination with TKIs in order to improve their effect in specific clinical settings. PML pathway and ATO ATO, an ancient drug used in traditional Chinese medicine, possesses anticancer effects in the treatment of acute promyelocytic leukemia (APL) [84]. In APL, ATO promotes degradation of the oncogenic PML-Retinoic Acid Receptor-a protein, therefore leading to the eradication of the disease. Beside the function of PML as a Retinoic Acid Receptor-a partner in APL, PML plays an essential role as a tumor suppressor in different tumors. Notably, PML is also involved in the regulation of malignant hematopoiesis in CML [79]. In particular, PML was shown to control CML leukemia stem cell maintenance. Importantly, ATO-induced PML degradation was associated with the exhaustion of CML in murine models [79]. Recently, PML was also shown to regulate the activity of PTEN in CML, suggesting that ATO could exhibit different anti-leukemic effects in CML [85]. In line with these considerations, several clinical trials have been 7.1

8

registered for the study of ATO in CML. One Phase I study aims to define the safety of the combination of ATO with tyrosine kinase inhibitors and whether these combinations could impact on the survival of CML LSC (NCT01397734; Table 3). The most challenging issue of this study, however, is to investigate whether the association ATO with TKIs could promote CML LSC exhaustion and therefore promoting CML eradication. Other studies proposed to investigate the efficacy of ATO in relapsed CML (NCT00005618) and have already been completed, although outcomes have yet to be reported. mTOR inhibitors The mTOR is one of the major regulator of tumorigenesis due to its capability to promote cell growth and cellular proliferation [86]. mTOR activation reflects the sustained PI3K/ AKT signaling which is driven by BCR-ABL [87]. Different mTOR inhibitors have been reported as promising drugs in experimental models. One recent clinical trial has been proposed using RAD001 (everolimus) in combination with imatinib to specifically target LSC (NCT01188889, Table 3); at 7.2



the time of this review, recruitment has not started yet. One additional clinical trial has been recently completed with the intention to combine everolimus with imatinib in the treatment of cytogenetically resistant CML (NCT00093639). Results still have to be reported.

MEK inhibitors Among signaling transduction inhibitors, MEK inhibitors have been reported to play a potential role both in the regulation of CML cellular proliferation and in mediating resistance to apoptosis [88,89]. One compound, MEK 162, is under investigation in association with nilotinib in advanced CML (NCT02225574, Table 3). Furthermore, another clinical trial (NCT00131989) has been designed to evaluate the efficacy of sorafenib in CML. Sorafenib is not a direct MEK inhibitor but, acting as a RAF inhibitor, is a MEK upstream regulator. Data from this trial still have to be reported.


7.3

5-LO inhibitors Arachidonate 5-LO gene (Alox5) is physiologically involved in the lipid metabolism and also plays a role in response to oxidative stress, in inflammation and cancer. Alox5 gene has been reported to exert a critical regulatory effect on CML stem cells. In homozygous Alox-5 knockout mice, the absence of Alox5 prevented BCR-ABL-induced CML with no effect on normal hematopoiesis. In CML mice, the Alox5 inhibitor Zileuton was more effective than imatinib in prolonging survival and the association of the two drugs was better than each drug as single agent [80]. A Phase I clinical trial of Zileuton in association with dasatinib is currently recruiting patients (NCT02047149, Table 3). 7.4

JAK2 inhibitors in CML BCR-ABL transforming potential was shown to require the activation of JAK2/STAT5 pathway, as recently reviewed [90]. In particular, in a kinase-independent manner, BCR-ABL promotes JAK2 recruitment to activate b-catenin signaling [91]. Notably, another report showed that STAT5 inhibition had synergic effects with TKI inhibitors in inducing progenitor CML cell death in vitro [92]. The observations on the relevance of JAK2/STAT5 in BCR-ABL signaling revealed challenging therapeutic implications due to the clinical availability of specific JAK2 inhibitors. In line with these considerations, several reports have described JAK2 inhibitors efficacy in CML murine models and cellular models [90,93]. Clinical trials are now recruiting patients to assess the efficacy of JAK2 inhibitors, and in particular ruxolitinib, in combination with TKI inhibitors to target CML stem cells (NCT01751425 and NCT01914484 clinical trials); a different JAK2 inhibitor, TC-02 citrate, is also being tested as a single agent in CML blast phase (NCT01204164, Table 3). 7.5

7.6

Aurora kinases inhibitors Tozasertib

7.6.1

Tozasertib (also known as MK-0457 or VX-680) is a panAurora kinase inhibitor. Aurora kinases are serine/threonine protein kinases that regulate cellular mitosis and chromosome stability [94]. Aurora kinases are found over-expressed in several hematologic cancers, including CML. Tozasertib was shown to potently inhibit Aurora kinases but also FLT-3, JAK2 and ABL [95]. Notably, it has been recently shown that tozasertib displays effective therapeutic properties in T315I-mutated CML [95]. Unfortunately, adverse effects are still significant and suggest that more selective inhibitors should be developed. Danusertib Danusertib hydrochloride (PHA-739358) is a pan-Aurora kinase inhibitor that promotes apoptosis of T315I BCR-ABL + cells [96]. A Phase II clinical trial (NCT00335868) has been designed to test whether Danusertib works in the CML patients that relapsed after imatinib treatment. The recruitment status and trial results are unknown. 7.6.2

7.7

Novel ABL kinase inhibitors Bafetinib

7.7.1

Bafetinib (NS-187, INNO-406) targets both ABL kinases and the SRC family kinase Lyn. Lyn was shown to promote imatinib resistance [97,98]. Interestingly, bafetinib inhibits most of the imatinib-resistant BCR-ABL point mutations but not the T315I mutation [99]. This drug is now under investigation in a Phase II clinical trials, after a promising Phase I study. Rebastinib Rebastinib (DCC-2036) is another challenging ABL inhibitor that displays activity even towards T315I mutation. DCC-2036 affects the switch between inactive and active conformations of BCR-ABL, and therefore, it is active against clinically relevant BCR-ABL mutations [100]. A multi-centre Phase I study (NCT00827138) has been proposed to study rebastinib efficacy in Ph+ CML with T315I mutation. This study has been completed but results are not reported. 7.7.2

GNF-5 In the search of overcoming resistance to ATP-binding site inhibitors of BCR-ABL, GNF-2 and its analogous GNF-5 were reported to affect the dynamics of the BCR-ABL ATP binding site through the biding to the myristate-binding site [101]. These drugs have shown to be highly effective in the association with imatinib or nilotinib, in vitro and in mouse models [101]. To our knowledge, no clinical trials are currently investigating these drugs. 7.7.3

Immunomodulating drugs A role for immunologic response in the control of CML has been first demonstrated by the typical graft-versus leukemia effect observed after allogeneic bone marrow transplantation, 7.8


9

C. Fava et al.


and is also involved in the clinical activity of IFN. Even in the TKIs era, attempts to exploiting the immunologic system in deepening and consolidating the response to BCR-ABL inhibitors remain attractive. Reactivation of immune response against tumor may be obtained by the block of inhibitory receptors on the T lymphocyte surface, such as the programmed cell death (PD1) receptor [83]. Anti-PD1 monoclonal antibodies such as nivolumab have been used in melanoma and renal cancer and are now investigated in Phase I trial in association with dasatinib (NCT02011945, Table 3). 8.

Potential development issues

As highly active drugs are available for the treatment of CML, it is going to be difficult to improve on treatment of the patients still facing a treatment failure or a suboptimal response. One issue is that the results we have achieved so far are so good that too many patients and too long followup would be needed to demonstrate better outcomes. Searching the mechanisms of resistance to TKIs, one important observation was that CML cells, and particularly LSC, may be insensitive to TKIs in a BCR-ABL-independent manner [102-105]. This is a critical aspect, suggesting that the cure of CML must be obtained with a combination therapy. However, the association of TKIs with other drugs will be possible only if a synergistic effect can be obtained without excess of toxicity, which is a major concern in the setting of a disease in which current treatments already allow patient in CP a very high life expectancy and a good QoL [106]. On the other hand, combined treatment under study will possibly offer new options for patients still presenting as or evolving to accelerated and blast phase, who still face a disease with a poor outcome. 9.

Conclusion

At this moment, imatinib and two second-generation TKIs, nilotinib and dasatinib are approved for first-line treatment of CML and two more drugs (bosutinib and ponatinib) are available for resistant/intolerant patients, giving the chance for a patient-adapted therapy, tailored on the basis of comorbidities, prognostic factors, and on the different mutations (finally including the T315I) and degree of tolerability. However, a number of patients with resistance to TKIs or showing multiple intolerance still exist as well as the unresolved problem of patients presenting as accelerated or blast phase (which are not the subject of this review). CML remains a unique model for improving target therapy of neoplastic disorders. Therefore, basic research and clinical trials are still exploring the possibility of association therapies with drugs targeting other pathways and different mechanism of blocking BCR/ ABL oncogenic activity emerging during the course of the therapy. 10

10.

Expert opinion

A good treatment of CML patients requires a careful follow-up, which is based on cytogenetic and molecular monitoring, in order to identify early signs of resistance and prevent the progression of the disease. In early CP, we can choose between imatinib and second-generation TKIs (nilotinib and dasatinib). In clinical trials, second-generation TKIs showed higher rates of early and deep molecular response, including MR4.5, and a reduced risk of progression compared to imatinib, without a clear-cut improvement in PFS and OS (a tendency to increase OS has been reported only for nilotinib 400 mg b.i.d. versus imatinib [p = 0.04] in the ENESTnd trial) [42]. So, the choice among these drugs as first-line treatment should mainly rely on the need of early response versus the expected toxicity which is evaluated on the basis of comorbidities. In second-line, mutational analysis is needed to drive the change of TKI, and this probably will be implemented by more sensitive type of analysis [107]. Nowadays CML is treated with lifelong administration of TKIs. The psychological and economical burden of such treatment is very high, and QoL can be reduced especially in young patients, who aim to discontinue the treatment. Also, some side effects may accumulate over time and the impact of treatment for longer periods of time is still unknown. However, survival data are very encouraging and demonstrate that TKIs remain very well tolerated drugs with a striking efficacy and safety as antineoplastic drugs. On the other hand, the increasing prevalence of the disease and the need of long-term therapy for patients with increasing median age and number of comorbidities, make the search of drugs with different safety profile and mechanism of action a major challenge. A number of clinical trials are ongoing to show how the available agents can be optimized in order to achieve higher rates of deep MR, which may correlate with longer durations of response and is required for a safe discontinuation of therapy. In spite of the outstanding progress obtained in the treatment of CML, the possibility of ‘cure’ is still debated, as many data coming from long-term experience with allogeneic stem cell transplantation and from patients treated with IFN in the late 1980s showed that a longterm remission is possible, but molecular recurrence of the disease can occur also after many years. This clinical observation is paralleled by many experimental evidences showing that CML stem cells are not eradicated by standard TKI treatment [81]. A main question still on the table is whether we need the LSC eradication, or if immunological reactivation may be sufficient for lifelong control of the disease once drug treatment has induced a deep reduction in leukemic cells burden. The scientific community is now evaluating if the association of other experimental drugs directed to several signaling transduction pathways of BCR-ABL, that mediates cellular proliferation and survival, can improve the efficacy on LSC, and on resistant cases, keeping in mind the issues of PFS, long-term safety, QoL and the need for treatment -- free remission.



Declaration of interest G Saglio is consultant for Novartis, Bristol Myers and ARIAD. The authors have no relevant affiliations or financial involvement with any organization or entity with a Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.


1.

Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. Philadelphia chromosomepositive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003;138:819-30

2.

Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin Cancer Res 2012;18:930-7

3.

Tsushima H, Iwanaga M, Miyazaki Y. Late effect of atomic bomb radiation on myeloid disorders: leukemia and myelodysplastic syndromes. Int J Hematol 2012;95:232-8

4.

5.

11.

Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872-84 Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349:1423-32

discontinuation in patients with CML. Blood 2013;121:3818-24 20.

Rix U, Hantschel O, Durnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 2007;110:4055-63

21.

Sacha T. Imatinib in chronic myeloid leukemia: an overview. Mediterr J Hematol Infect Dis 2014;6:e2014007

12.

Cross NC, White HE, Muller MC, et al. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 2012;26:2172-5

22.

Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-17

13.

23.

Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol 2009;22:295-302

Chronic myelogenous leukemia, NCCN Guidelines. Available from: http://www. nccn.org/professionals/physician_gls/pdf/ cml.pdf; (Version 3.2014)

14.

Smith AG, Painter D, Howell DA, et al. Determinants of survival in patients with chronic myeloid leukaemia treated in the new era of oral therapy: findings from a UK population-based patient cohort. BMJ Open 2014;4:e004266

Quintas-Cardama A, Jabbour EJ. Considerations for early switch to nilotinib or dasatinib in patients with chronic myeloid leukemia with inadequate response to first-line imatinib. Leuk Res 2013;37:487-95

Deininger M, Guilhot F, Goldman JF, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood 2009;114:1126

24.

15.

Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCRABL1 decline. Blood 2014;124:511-18

De Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:3358-63

16.

Hanfstein B, Shlyakhto V, Lauseker M, et al. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia 2014;28:1988-92

25.

Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 2011;29:1634-42

17.

Breccia M, Alimena G. Discontinuation of tyrosine kinase inhibitors and new approaches to target leukemic stem cells: treatment-free remission as a new goal in chronic myeloid leukemia. Cancer Lett 2014;347:22-8

26.

Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010;363:2511-21

27.

Deininger MW, Kopecky KJ, Radich JP, et al. Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 2014;164:223-32

6.

Baccarani M, Castagnetti F, Gugliotta G, et al. Treatment recommendations for chronic myeloid leukemia. Mediterr J Hematol Infect Dis 2014;6:e2014005

7.

Kantarjian HM, O’Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003;97:1033-41

8.

Oriana C, Martin H, Toby P, et al. Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: a case study for technology appraisal on the basis of surrogate outcomes evidence. Value Health 2013;16:1081-90

9.

10.

financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Akwaa F, Liesveld J. Surrogate end points for long-term outcomes in chronic myeloid leukemia. Leuk Lymphoma 2013;54:2103-11

18.

Apperley J. CML in pregnancy and childhood. Best Pract Res Clin Haematol 2009;22:455-74

19.

Branford S, Yeung DT, Ross DM, et al. Early molecular response and female sex strongly predict stable undetectable BCRABL1, the criteria for imatinib Expert Opin. Emerging Drugs (2015) 20(2)

11

C. Fava et al.

28.


29.

30.

Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 2010;28:424-30

influence overall and event-free survival. Leuk Res 2014;38:1173-6 37.

Jabbour EJ, Cortes JE, Kantarjian HM. Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: a clinical perspective and emerging treatment options. Clin Lymphoma Myeloma Leuk 2013;13:515-29

Baccarani M, Rosti G, Castagnetti F, et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphiapositive chronic myeloid leukemia: a European LeukemiaNet Study. Blood 2009;113:4497-504

38.

Proetel U, Pletsch N, Lauseker M, et al. Older patients with chronic myeloid leukemia (‡65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV. Ann Hematol 2014;93:1167-76

39.

Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 2011;117:1141-5

40.

Le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 2012;26:1189-94

41.

Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010;362:2251-9 Paper leading to the approval of nilotinib as front-line therapy.

31.

Breccia M, Loglisci G, Salaroli A, et al. Delayed cytogenetic and major molecular responses associated to increased BMI at baseline in chronic myeloid leukemia patients treated with imatinib. Cancer Lett 2013;333:32-5

32.

O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004

..

42.

Soverini S, Colarossi S, Gnani A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006;12:7374-9

Saglio G, Hochhaus A, Hughes TP, et al. ENESTnd update: nilotinib (NIL) vs imatinib (IM) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and the impact of early molecular response (EMR) and sokal risk at diagnosis on long-term outcomes. Blood 2013;122:92

33.

Efficace F, Baccarani M, Breccia M, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood 2011;118:4554-60

34.

Efficace F, Baccarani M, Breccia M, et al. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia 2013;27:1511-19

43.

Latagliata R, Ferrero D, Iurlo A, et al. Imatinib in very elderly patients with chronic myeloid leukemia in chronic phase: a retrospective study. Drugs Aging 2013;30:629-37

Hochhaus A, Saglio G, Larson RA, et al. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2013;121:3703-8

44.

Hughes TP, Hochhaus A, Kantarjian HM, et al. Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on frontline imatinib or nilotinib 300 mg twice daily. Haematologica 2014;99:1204-11

35.

36.

12

Breccia M, Luciano L, Latagliata R, et al. Age influences initial dose and compliance to imatinib in chronic myeloid leukemia alderly patients but concomitant comorbidities appear to


45.

Hughes TP, Lipton JH, Spector N, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood 2014;124:729-36

46.

Kim TD, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013;27:1316-21

47.

Rea D, Mirault T, Cluzeau T, et al. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematologica 2014;99:1197-203

48.

Racil Z, Razga F, Drapalova J, et al. Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica 2013;98:e124-6

49.

Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010;95:232-40

50.

Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 2014;123:2317-24

51.

Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012;119:1123-9

52.

Cortes JE, Hochhaus A, Kim DW, et al. Four-year (Yr) follow-up of patients (Pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib or imatinib: efficacy based on early response. Blood 2013;122:653 Last update of the DASISION study.

..

53.

Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012;120:3898-905

54.

Paydas S. Dasatinib, large granular lymphocytosis, and pleural effusion: useful or adverse effect? Crit Rev Oncol Hematol 2014;89:242-7



55.

Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009;114:261-3

56.

Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:2128-37

57.

Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosomepositive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011;118:4567-76

58.

59.

60.

..

61.

62.

63.

..

64.

65.

66.

67.

Chuah C, Guerci-Bresler A, Rosti G, et al. EPIC: a phase 3 trial of ponatinib vs imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CP-CML). Haematologica 2013;99:238 Le Coutre PD, Kim DW, Pinilla-Ibarz J, et al. Ponatinib in heavily pretreated patients with chronic phase chronic myeloid leukemia (CP-CML): management of adverse events (AEs). Blood 2013;122:1496 Kim SH, Menon H, Jootar S, et al. Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Haematologica 2014;99:1191-6

Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012;119:3403-12

68.

Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 2012;30:3486-92

Talpaz M, Hehlmann R, Quintas-Cardama A, et al. Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia. Leukemia 2013;27:803-12

69.

Simonsson B, Gedde-Dahl T, Markevarn B, et al. Combination of pegylated IFN-alpha2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood 2011;118:3228-35

Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 2014;123:1309-18 Last update on the management of toxicities with bosutinib.

70.

O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401-12 Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012;367:2075-88 Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013;369:1783-96 Ponatinib changed the outcome of CML patients with T315I mutation. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. Ponatinib in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL

omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 2012;120:2573-80

mutation: 2-year follow-up of the PACE trial. Blood 2013;122:650

71.

72.

73.

Cortes J, Quintas-Cardama A, Jones D, et al. Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia: a randomized trial of frontline high-dose imatinib mesylate with or without pegylated interferon alpha-2b and granulocyte-macrophage colonystimulating factor. Cancer 2011;117:572-80 Allan EK, Holyoake TL, Craig AR, Jorgensen HG. Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukemia 2011;25:985-94 Cortes J, Digumarti R, Parikh PM, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronicphase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 2013;88:350-4

74.

Cortes JE, Nicolini FE, Wetzler M, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib. Clin Lymphoma Myeloma Leuk 2013;13:584-91

75.

Huang X, Cortes J, Kantarjian H. Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer 2012;118:3123-7

76.

Howlader Nea. SEER Cancer Statistic Review, 1975-2010. National Cancer Institute, Bethesda; 2013. Available from: http//seer.cancer. gov/csr/1975_2010/; Based November 2012 SEER Data Submission, posted to SEER webstite April 2013.

77.

Lauseker M, Hasford J, Pfirrmann M, Hehlmann R. The impact of health care settings on survival time of patients with chronic myeloid leukemia. Blood 2014;123:2494-6

78.

Loveman E, Cooper K, Bryant J, et al. Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinibresistant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess 2012;16:iii-xiii; 1-137

79.

Ito K, Bernardi R, Morotti A, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008;453:1072-8

80.

Chen Y, Hu Y, Zhang H, et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet 2009;41:783-92

81.

Morotti A, Panuzzo C, Fava C, Saglio G. Kinase-inhibitor-insensitive cancer stem cells in chronic myeloid leukemia. Expert Opin Biol Ther 2014;14:287-99

82.

Steelman LS, Pohnert SC, Shelton JG, et al. JAK/STAT, Raf/MEK/ERK, PI3K/ Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 2004;18:189-218

83.

Aranda F, Vacchelli E, Eggermont A, et al. Trial watch: immunostimulatory

Cortes J, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous Expert Opin. Emerging Drugs (2015) 20(2)

13

C. Fava et al.

therapy effectively eliminates TKIinsensitive CML stem/progenitor cells. Oncotarget 2014;5:8637-50

monoclonal antibodies in cancer therapy. Oncoimmunology 2014;3:e2729 84.

85.


86.

87.

88.

89.

Kritharis A, Bradley TP, Budman DR. The evolving use of arsenic in pharmacotherapy of malignant disease. Ann Hematol 2013;92:719-30 Morotti A, Panuzzo C, Crivellaro S, et al. BCR-ABL disrupts PTEN nuclearcytoplasmic shuttling through phosphorylation-dependent activation of HAUSP. Leukemia 2014;28:1326-33 Lv X, Ma X, Hu Y. Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment. Expert Opin Drug Discov 2013;8:991-1012

95.

96.

Moore AS, Blagg J, Linardopoulos S, Pearson AD. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia 2010;24:671-8 Seymour JF, Kim DW, Rubin E, et al. A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia. Blood Cancer J 2014;4:e238 Gontarewicz A, Balabanov S, Keller G, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCRABL mutations including T315I. Blood 2008;111:4355-64

Redig AJ, Vakana E, Platanias LC. Regulation of mammalian target of rapamycin and mitogen activated protein kinase pathways by BCR-ABL. Leuk Lymphoma 2011;52(Suppl 1):45-53

97.

Pellicano F, Simara P, Sinclair A, et al. The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. Leukemia 2011;25:1159-67

Wu J, Meng F, Kong LY, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst 2008;100:926-39

98.

O’Hare T, Eide CA, Deininger MW. Persistent LYN signaling in imatinibresistant, BCR-ABL-independent chronic myelogenous leukemia. J Natl Cancer Inst 2008;100:908-9

99.

Santos FP, Kantarjian H, Cortes J, Quintas-Cardama A. Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. Curr Opin Investig Drugs 2010;11:1450-65

Packer LM, Rana S, Hayward R, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell 2011;20:715-27

90.

Warsch W, Walz C, Sexl V. JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia. Blood 2013;122:2167-75

91.

Neviani P, Harb JG, Oaks JJ, et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest 2013;123:4144-57

92.

Schafranek L, Nievergall E, Powell JA, et al. Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia. Leukemia 2015;29:76-85

93.

Lin H, Chen M, Rothe K, et al. Selective JAK2/ABL dual inhibition

14

94.

100. Chan WW, Wise SC, Kaufman MD, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 2011;19:556-68 101. Zhang J, Adria´n FJ, Jahnke W, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 2010;463:501-6 102. O’Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of


..

targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer 2012;12:513-26 Review on the advances on CML stem cell biology possibly leading to association therapies.

103. Crews LA, Jamieson CH. Selective elimination of leukemia stem cells: hitting a moving target. Cancer Lett 2013;338:15-22 104. Sinclair A, Latif AL, Holyoake TL. Targeting survival pathways in chronic myeloid leukaemia stem cells. Br J Pharmacol 2013;169:1693-707 105. Sweet KL, Hazlehurst LA, Pinilla-Ibarz J. The one-two punch: combination treatment in chronic myeloid leukemia. Crit Rev Oncol Hematol 2013;88:667-79 106. Ahmed W, Van Etten RA. Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond. Hematology Am Soc Hematol Educ Program 2013;2013:189-200 107. Machova Polakova K, Kulvait V, Benesova A, et al. Next-generation deep sequencing improves detection of BCRABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase. J Cancer Res Clin Oncol 2014. [Epub ahead of print] 108. National Cancer Insitute clinical trials. as of October 2014. Available from: https://www.clinicaltrials.gov/ct2/results? recr=Open&no_unk=Y&cond=% 22Leukemia%2C+Myelogenous%2C +Chronic%2C+BCR-ABL+Positive%22

Affiliation

Carmen Fava†, Alessandro Morotti, Irene Dogliotti, Giuseppe Saglio & Giovanna Rege-Cambrin † Author for correspondence University of Turin, San Luigi Hospital, Department of Clinical and Biological Sciences, Orbassano 10043, Italy E-mail: [email protected]

Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring.

Emerging therapies for acute myeloid leukemia.

Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice.

Hypoparathyroidism - disease update and emerging treatments.

Bosutinib for Chronic Myeloid Leukemia.

Emerging treatments for chronic hepatitis C.

Chronic myeloid leukemia and chronic lymphocytic leukemia.

Update on treatments for dystonia.

Current and emerging monoclonal antibody treatments for chronic lymphocytic leukemia: state of the art.

Tyrosine kinase inhibitor therapy in chronic myeloid leukemia: update on key adverse events.

Update on antigen-specific immunotherapy of acute myeloid leukemia.

Acute myeloid leukemia: 2014 update on risk-stratification and management.

An Overview and Update of Chronic Myeloid Leukemia for Primary Care Physicians.

Chronic myeloid leukemia: room for improvement?

Emerging immunological drugs for chronic lymphocytic leukemia.

Treatment recommendations for chronic myeloid leukemia.

Midostaurin: an emerging treatment for acute myeloid leukemia patients.

Optimized Treatment Schedules for Chronic Myeloid Leukemia.

Chronic myeloid leukemia in India.

Splenectomy in chronic myeloid leukemia.

Emerging treatments for amyloidosis.

Epidemiology of chronic myeloid leukaemia: an update.

AKT-induced reactive oxygen species generate imatinib-resistant clones emerging from chronic myeloid leukemia progenitor cells.

First-line treatment of newly diagnosed elderly patients with chronic myeloid leukemia: current and emerging strategies.