Rosti-2017-Tyrosine kinase inhibitors in chron.pdf

Currently,the tyrosine kinase inhibitor(TKI)imatinib is the gold standard therapy for the treatment of chronic myeloid leukaemia(CML).Imatinib was the first TKI that was approved in CML,and dramatically increased the overall survival of patients with CML,to levels not yet improved upon by the first-line treatment with second-generation TKIs16.Around 30%of the patients,however,develop resistance to treatment with the stand-ard dose of imatinib(400 mg daily).Inthe past decade,strategies to improve therapy for such patients were based predominantly on the optimization of imatinib administration(for example,increasing the dose).The development and approval of second-generation and third-generation TKIs(dasatinib,nilotinib,bosutinib,and ponatinib)led to a wider availability of therapeutic agents for second-line and third-line therapy710.At pres-ent,in many countries,imatinib,nilotinib and dasatinib are registered for first-line treatment,whereas ponati-nib and bosutinib are approved only as rescue strat egies.Approximately,3050%of the patients who receive imatinib as frontline treatment will remain on long-term(5years)treatment with this agent;conversely,a large proportion of patients(5070%)will require treatment with a second-line or third-line agent610.Thus,long-term(5years)survival does not depend exclusively on the choice of first-line agent,but also on the availability and proper implementation of TKIs beyond first-line.In this Review,we discuss the debatable and difficult choice of first and subsequent lines of treatment that physicians face when treating patients with CML.Agents for frontline treatment of CMLImatinibImatinib was the first TKI to be approved by the FDA for the treatment of patients with CML1,5.Imatinib inhibits the kinase activity of the fusion protein BCRABL1encoded by a gene mutated in all patients with Philadelphia-chromosome-positive(Ph+)CML1,46through a competitive mechanism at the ATP-binding site.In addition,imatinib inhibits the activity of other tyrosine kinases relevant to lymphocyte function,such as PGDFR,and the mast/stem cell growth factor receptor Kit10(TABLE1).The IRIS study1,5,6 was the first clinical trial to establish that patients with CML can benefit from treatment with TKIs.In this phaseIII trial,patients with CML(n=1,106)were randomly assigned to receive standard-dose imatinib(400 mg daily),or IFN in combination with low-dose cytarabine(the standard-of-care treatment at that time).After a median follow-up of 19months,the outcomes for patients who received imatinib were significantly better than patients receiving IFN plus cytarabine.Of note,the complete Institute of Haematology and Medical Oncology Lorenzo edAriosto Sergnoli,Department of Experimental,Diagnostic and Specialty Medicine,Bologna University School of Medicine,S.Orsola-Malpighi University Hospital,Via Massarenti 9,40138 Bologna,Italy.Correspondence to G.R.gianantonio.rostiunibo.itdoi:10.1038/nrclinonc.2016.139Published online 18 Oct 2016Tyrosine kinase inhibitors in chronic myeloid leukaemia:which,when,forwhom?Gianantonio Rosti,Fausto Castagnetti,Gabriele Gugliotta and Michele BaccaraniAbstract|The therapeutic armamentarium for chronic myeloid leukaemia(CML)comprises mainly tyrosine kinase inhibitors(TKIs),with several agents available for frontline treatment,or for the treatment of disease resistance or intolerance to the first-choice or second-choice drug.Theavailability of different drugs is a major achievement,but means that choices must be madewhich can be difficult and questionable at times.The most important end point considered in decision-making regarding treatment for any cancer is overall survival,but additional factors(such as age,prognostic category,safety,or the possibility of achieving treatment-free remission)should be considered when selecting an agent for frontline treatment.Regardless of the TKI selected for first-line treatment,guidelines that define the importance of reaching specific response indicators and procedures for vigilant follow-up monitoring are established to ensure timely implementation of second-line TKIs.Herein,we discuss the benefits and risks of the different TKIs available for the treatment of patients with CML,and how to decide when to employ these agents at different treatment settings.NATURE REVIEWS|CLINICAL ONCOLOGY VOLUME 14|MARCH 2017|141REVIEWS 2016 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.cytogenetic response rates(CCyR;BOX1)were 74%for imatinib compared with 9%(P 0.001)for IFN plus cytarabine,and the freedom from disease progression to the accelerated or blast phase at 12months was 99%and 93%(P 0.001),respectively.An update of this study at 6years of follow up6 showed durable responses,with event-free survival(EFS)and overall survival(consid-ering only CML-related deaths)rates of 81%and 93%,respectively,for patients who received imatinib.No updated data on patients randomized to the IFN plus cytarabine arm were reported.In other studies of imati-nib conducted in the past 10years2,3,5,1118,very high over-all survival rates were reported(8597%)at variable time points(26.5years)and the rate of disease progression from chronic phase to accelerated or blast phase was generally below 10%.Some patients(4050%)did not respond to imatinib treatment owing to the emergenceof primary resistance(failure to achieve predefined levels of response)or secondary resistance(loss of a previously achieved level of response),or of adverse events;in this situation,patients could respond to timely second-line treatments,as discussed later.The inhibitory effect of imatinib on the BCRABL1 kinase is less potent than that of nilotinib and dasatinib(TABLE1).The lower inhibitory effect of imatinib,owing to insufficient kinase inhibition,can explain some of the observed treatment failures,as reported in invitro and/or invivo studies1923.Clinical evidence for the sub-optimal efficacy of imatinib comes from the observation that a failure to achieve adequate blood concentrations(plasma trough levels 1,000ng/ml)is associated with a poor response22,23.Similarly,how imatinib is transported inside and outside the cell,and determining appropriate intra cellular imatinib levels,are crucial.In particular,the influx of imatinib is actively mediated by the organic cation transporter 1(OCT-1)2427 protein;low OCT-1 activity has been associated with a poor response2527.The outgrowth of subclones harbouring mutations in the kinase domain of BCRABL1 was reported more frequently after treatment with imatinib compared with nilotinib and dasatinib79,19,20,which represents another drawback for the use of imatinib as first-line therapy2,3,2832.These mutations can disrupt the bind-ing of inhibitors to the TKIs,resulting in an insufficient inhibitory effect.Indeed,mutations affecting BCRABL1 are the most common(3070%,depending on disease phase),and also the best characterized determinants of resistance to TKIs33.In three prospective randomized trials,BELA34,ENESTnd35 and DASISION36,imatinib was compared with bosutinib,nilotinib and dasatinib in patients with chronic-phase CML who had not received prior TKI therapy.In all trials,the number of mutations leading to treatment resistance was generally twofold higher in patients treated with imatinib compared with those treated with second-generation TKIs.Finally,the most-effective imatinib schedule administration has not been established:more-frequent doses(400 mg twice daily(b.i.d.)11,13,37 induce more-rapid responses than the standard doses(400 mg daily),but are not clearly associ ated with better outcomes,and are linked to higher haemato logical and extra-haematological toxi-city.In 2011,results from the CML-IV study38 demon-strated that a high-dose patient-adapted strategy induced higher rates of molecular response(MR;BOX1)compared with standard treatment schedules:the major molecular response(MMR)at 12months,with tolerability-adapted imatinib 800 mg daily versus 400 mg daily was 59%and 44%(P 80 amino acid sub-stitutions reported in association with resistance to imati-nib10(TABLE2)39.The findings of two phaseII studies40,41 showed more-efficient and more-rapid responses in patients with CML treated with frontline nilotinib(400 mg b.i.d.)in a historical comparison with imati-nib.Subsequently,in the phaseIII ENESTnd trial35,the effect of nilotinib at two doses(300 mg or 400 mgb.i.d.)was compared with that of imatinib(400 mg daily).The primary end point,MMR at 12months,was reached with nilotinib at both dose levels in 44%and 43%of patients,respectively,but only in 22%of patients treated with imatinib(P 0.001).Moreover,a reduced rate of progression to accelerated or blast phase was observed with nilotinib,and the 5-year follow-up results of the trial2 showed progression-free survival(PFS)rates of 95.8%and 92.2%for the 400 mg b.i.d.and 300 mg b.i.d.doses of nilotinib,respectively,compared with 91%with imatinib(P=0.02 and P=0.69,respectively).Despite the lower risk of disease transformation observed at 5years for nilotinib(400 mg b.i.d.),a survival advantage was not observed(all deaths considered).The overall survival rate(only deaths related to advanced-stage CML),however,was significantly higher for patients receiving nilotinib 400 mg b.i.d.(97.7%)and 300 mg b.i.d.(98.5%)than for those receiving imatinib(93.8%;P=0.029 and P=0.005,respectively).The patients who Key points Several tyrosine kinase inhibitors(TKIs)are currently available for patients with chronic myeloid leukaemia(CML)at different stages of the disease Different end points,such as survival,treatment-free remission or response milestones,can guide the selection of the most appropriate TKI;other factors(for example,age,prognostic category or safety)should also be considered Imatinib is the gold standard therapy for the treatment of CML and is already available as a generic drug in many countries,but a considerable proportion of patients develop resistance or intolerance to this drug Nilotinib,dasatinib,bosutinib and ponatinib are TKIs with a higher inhibitory action than imatinib,but also associated with different safety profilesREVIEWS142|MARCH 2017|VOLUME 14 2016 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.received 300 mg b.i.d.had lower frequencies of adverse events and treatment-related discontinuation than those receiving 400 mg b.i.d.Thus,300 mg b.i.d.is currently the dose approved for first-line treatment10,35.Nilotinib induces deep molecular responses(also referred to as MR4.5;BOX1)more frequently than imatinib:after a minimum follow-up time of 5years2,the MR4.5 rate(cumulative probability)was higher for patients treated with 300 mg b.i.d.nilotinib than for those who received imatinib(54%versus 31%;P 0.001).The results of the ENESTchina trial42 confirmed the superiority of nilo-tinib 300 mg b.i.d.over imatinib 400 mg daily in terms of MMR rates at 12months and 24months of treatment;the absolute difference between the MMR rates was 25.1%at 12months(P 0.0001)lower frequency of cardio vascular adverse events compared with patients with a high or very high risk48,52,indicating the need for caution when treating the lattergroups.DasatinibDasatinib is an oral,second-generation TKI with a 350-fold higher BCRABL1 inhibitory activity invitro than imatinib8,9.Dasatinib also inhibits kinases from the Src family,which might be important in blunting signal-ling pathways that are critical in CML cells53.100 mg daily is the registered dasatinib dose for the treatment ofCML in the early chronic phase,owing to the resultsof the piv-otal randomized trial,DASISION3,36,54,which compared the effect of frontline dasatinib 100 mg daily with imati-nib 400 mg daily.The primary end point of the study was Table 1|Main characteristics of the TKIs registered for treatment of CMLCharacteristicsImatinibNilotinibDasatinibBosutinibPonatinibStandard dose,first line400mg daily300mg b.i.d.100mg dailyNANADose,second and further lines300400 mg b.i.d.400mg b.i.d.100mg daily500mg daily45mg dailyPlasma half-life20 h15 h5 h34 h19 hPlasma concentration(nM)Peak4,202 1,2722,329 772133 74392145 73Trough2,062 1,3341,923 1,2335.5 1.426864 29IC50(nM)BCRABL126067910250.81.8420.5PDGFR72752.93.01.1Kit992091810,00012Src1,0001,0000.13.05.4VEGFR-210,0003,720NANA1.5BTK5,000NA1.12.5849BCRABL1,BCRABL1 fusion protein;b.i.d.,twice daily;BTK,tyrosine-protein kinase BTK;Kit,mast/stem cell growth factor receptor Kit;NA,not applicable;PDGFR,platelet-derived growth factor receptor alpha;Src,tyrosine-protein kinase Src;VEGFR-2,vascular endothelialgrowth factor receptor 2.Reprinted from Baccarani,M.,Soverini,S.&DeBenedittis,C.2014 ASCO Educational Book 167175(ASCO,2014).Reprinted with permission American Society of Clinical Oncology.All rights reserved.REVIEWSNATURE REVIEWS|CLINICAL ONCOLOGY VOLUME 14|MARCH 2017|143 2016 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.a confirmed CCyR at 12months,which was achieved ina higher percentage of patients receiving dasatinib versus imatinib(77%versus 66%,P=0.007)36.Treatment with dasatinib was also associated with higher rates of MMR than imatinib(5-year cumulative MMRrates:76%and 64%for dasatinib and imatinib,respectively;P=0.022).The rate of disease progression was lower in the dasatinib arm of the trial,but no survival advan-tage has emerged3,36,54.The percentage of patients who remained on treatment at the time of reporting the 5-year update of the trial3 was 61%and 63%for dasatinib and imatinib,respectively.The rate of progression to acceler-ated and blastic phase with dasatinib and imatinib was 4.6%and7.3%,respectively.With regard to kinase domain mutations,in the DASISION trial55 a similar proportion of patients devel-oped mutations after treatment with imatinib or dasat-inib;these values are in contrast with those reported in the ENESTnd trial29(TABLE2).Trial withdrawal owing to adverse events was 16%in the dasatinib arm of DASISION,compared with 7%in the imatinib arm54.The tolerability profile of dasatinib is favourable compared with that of imatinib.Muscle and joint aches,fatigue,dermatological complaints,headaches,and diarrhoea are the most-common nonhaematological adverse events associated with dasatinib treatment.Pleural effusion,is commonly observed at rates of 2050%;in trials of dasatinib in the second-line setting56,57,19%of patients overall had this adverse effect.The frequencies for other common TKI-related nonhaematological adverse events were either lower for patients who received dasatinib than those treated with imatinib,or were similar for the two treatment groups3.The most important risk factor for pleural effusion is increasing age,and the presence of chronic obstructive lung disease.A trend was observed for a lower occurrence of pleural effusion with dasatinib 100 mg daily(7%)compared with 50 mg b.i.d.(11%),consistent withfindings from a dose-optimization study performed with dasatinib in patients with CML in the chr