management of tki resistance

8/18/2019 Management of Tki Resistance

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MANAGEMENT OF TKI RESISTANCE

A problem that may increase due to the idespread use o! all o! the commercially a"ailable TKIs

!or CM# is increased dru$ resistance% One o! the most common mechanisms o! resistance in"ol"es point

mutations in the &inase domain o! 'CR(A'#) hich impairs the acti"ity o! the a"ailable TKIs% Second

$eneration TKIs are able to o"ercome most o! the mutations that con!er resistance to imatinib) thou$h

no"el mutations renderin$ the leu&emia resistant to dasatinib and*or nilotinib ha"e emer$ed% Oneimportant mutation) the T+,-I) is &non as the .$ate&eeper/ mutation) as it displays resistance to all

currently a"ailable TKIs e0cept ponatinib%

'e!ore de!inin$ a patient as ha"in$ TKI(resistance and modi!yin$ therapy) treatment compliance

and dru$(dru$ interactions should be ruled out% Rates o! imatinib adherence ha"e been estimated to ran$e

!rom 1- to 234) and loer adherence rates correlated to orse outcome 5-36-78% In one study o! 91

patients ith CM#(C: treated ith imatinib ;33 m$ daily) adherence rate o! 234 or less resulted in

MMR in only 79%;4 as compared ith 2;%-4 in patients ith 3%33,? 5-38%

CMR rates ere 3 "s% ;+%94) respecti"ely) =:-3%337?) and no molecular responses ere obser"ed hen

adherence rates ere 934 or loer% #oer adherence rates ha"e been described in youn$er patients) those

ith ad"erse e!!ects o! therapy) and those ho ha"e re@uired dose escalations 5-38%

Second and third generation TKIs

'e!ore their appro"al to treat !irst(line CM#(C:) both nilotinib and dasatinib ere appro"ed !or

use in second(line CM#(C: !olloin$ prior therapy includin$ imatinib 5-+)-;8% Clinical studies o!

second(line and third line TKIs are summaried in Table III% 'ased on these clinical studies) se"eral

noteorthy ideas ha"e emer$ed% First) second(line treatment ith nilotinib or dasatinib can yield hi$h

rates o! response in patients ho ha"e inade@uate response to imatinib) includin$ hi$h rates o! MMR%

Second) dose escalation o! imatinib can impro"e response rates in patients ith inade@uate response to

standard(dose imatinib) but sitchin$ to second(line nilotinib or dasatinib can be more e!!ecti"e 5--8%

Se"eral studies that e"aluated second(line nilotinib 5-B)-18 or dasatinib 5-B)-98 and hi$h(dose imatinib

=;33 m$ 'I? ha"e demonstrated si$ni!icantly hi$her rates o! CDR) CCyR) and MMR ith the neerTKIs than ith hi$h(dose imatinib% Moreo"er) :FS in these studies as better ith the neer TKIs than

ith hi$h(dose imatinib% In addition) earlier sitch to second(line TKI may be more e!!ecti"e than later

sitch% In the TIE#(II study) patients ho had suboptimal response to imatinib and ere sitched ri$ht

aay to nilotinib had a hi$her rate o! CMR at ,7 months than patients ho had dose escalation o!

imatinib prior to bein$ sitched to nilotinib 5-28% In a retrospecti"e pooled analysis o! three clinical

studies o! second(line dasatinib !or patients resistant to or intolerant o! imatinib) patients ho ere

sitched to dasatinib a!ter the loss o! MCyR =early inter"ention $roup? had hi$her rates o! CDR) CCyR)

and MMR) as ell as 7;(month EFS) TFS) and OS) than patients ho ere sitched a!ter the loss o! both

MCyR and CDR =late inter"ention $roup? 5B38% Althou$h this analysis included studies ith distinct study

desi$ns and "arious dosin$ schedules o! dasatinib) the core !indin$ that earlier sitch to dasatinib as

associated ith better outcomes than later sitch as reasonably consistent%

'osutinib as initially studied in patients that ere resistant to or intolerant o! imatinib 5B,8%

A!ter a dose escalation period) -33 m$ once daily as selected to $o !orard as the phase II dose) ith

the potential !or dose escalation to B33 m$ once daily !or patients not meetin$ prespeci!ied benchmar&s%

There ere 799 patients enrolled in the pi"otal phase II trial) ith more than to thirds o! the patients

documented as ha"in$ imatinib(resistant disease% The primary endpoint as MCyR at B months) and this

as achie"ed in +,4 o! the patients treated% At any point durin$ !ollo up) ;,4 achie"ed a CCyR%


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'osutinib appeared to retain acti"ity across most &non mutations that con!er imatinib resistance) e0cept

!or the T+,-I% Responses ere independent o! hether patients ere resistant to or intolerant o! imatinib%

The most common to0icities noted ere diarrhea) nausea) "omitin$) and rash% iarrhea occurred in 9;4

o! the patients o"erall) ith 24 e0periencin$ an e"ent classi!ied as $rade + =there ere no $rade ; e"ents

documented?% Other notable ad"erse e"ents included myelosuppression and li"er !unction test

abnormalities%:onatinib is considered a third $eneration TKI) as it is the !irst compound in the class considered

to e0hibit acti"ity a$ainst CM# in the presence o! a T+,-I mutation 5B78% It is considered $reater than -33

times as potent than imatinib at inhibitin$ 'CR(A'# 5B+8% E"idence to support the appro"al o! ponatinib

as presented in the phase II :ACE trial) here ;;2 patients ith hea"ily pretreated CM# or :hiladelphia

chromosome(positi"e acute lymphoblastic leu&emia ere enrolled 5B;8% :atients ere considered !or this

trial i! they ere resistant to or intolerant o! dasatinib or nilotinib% Alternati"ely) any patient ith a T+,-I

mutation could be included% The dose o! ponatinib as ;- m$ once daily) and patients ere strati!ied by

phase o! disease and hether or not there as a T+,-I mutation% Focusin$ on the 7B1 patients ho

recei"ed ponatinib in the C:) -B4 achie"ed a MCyR by ,7 months) hich included 134 o! C: patients

ith a T+,-I mutation =n-;-?% :atients responded more !a"orably i! they had recei"ed !eer TKIs% The

most common ad"erse e"ents ere rash) dry s&in) and abdominal pain% Other notable to0icities in the

:ACE study included hypertension and pancreatitis% Serious e"ents possibly related to the dru$ included

arterial thrombotic e"ents) and the rate as reported to increase ith lon$er durations o! e0posure to

ponatinib% This led to a temporary suspension o! the sale o! ponatinib in the nited States) as ell as the

modi!ication or closure o! se"eral clinical trials% Re"ised labelin$ and a restricted access pro$ram ere

put in place alloin$ the manu!acturer to resume its mar&etin$%

How to select a second or third line option

At the time o! treatment !ailure) patients should under$o bone marro biopsy to allo proper

determination o! disease phase and documentation o! any clonal e"olution% All patients should ha"e their

CM# cells tested !or 'CR(A'# &inase domain mutations) as this ill help $uide the decision on hichTKI to select% asatinib and nilotinib retain acti"ity a$ainst most o! the &non mutations that con!er

resistance to imatinib 5B-)BB8% hen selectin$ beteen dasatinib and

nilotinib) in "itro and in "i"o data ha"e identi!ied distinct mutations that e0hibit decreased sensiti"ity to

each o! the a$ents 5B1)B98% The clinician may tend to !a"or dasatinib i! the patient has the !olloin$

mutations at the time o! disease pro$ression H7-+D) E7--K*) or F+-2C*% Alternati"ely) nilotinib may

be a better selection in the presence o! the 722# and F+,1# mutations% For patients lac&in$ these

mutations) the choice once a$ain calls into consideration to0icity pro!ile and cost%

The a"ailable data also indicate that bosutinib can be used !or patients ith most &non

mutations that lead to imatinib !ailure 5B,8% #i&e dasatinib and nilotinib) bosutinib lac&s acti"ity a$ainst

T+,-I% 'osutinib may be a reasonable choice !or patients ho !ail imatinib ho are not $ood candidates

!or dasatinib or nilotinib% 'osutinib has a relati"ely distinct to0icity pro!ile !rom the other TKIs) ith the

predominant problem bein$ diarrhea and other $astrointestinal complaints% Recently) an analysis as

conducted to closely characterie the to0icity o! bosutinib and the mana$ement strate$y 5B28%

iarrhea as documented in 974 o! the o"erall cohort =n--13?) the maJority o! hich as $rades ,*7 in

se"erity% Myelosuppression and li"er !unction test abnormalities ere also common% The authors !ound

that ith appropriate supporti"e care and monitorin$) most patients are able to continue on therapy ith

periodic dose interruptions or adJustment%


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:onatinib should be considered the a$ent o! choice !or any patient that de"elops a T+,-I mutation

and in instances here other TKIs are not indicated% There are currently no other commercially a"ailable

TKIs that ha"e acti"ity a$ainst this mutation% The ris& !or thrombotic e"ents ith ponatinib is serious) but

the bene!its outei$h the ris&s !or most patients ith a T+,-I mutation) as there are "ery !e "iable

options !or disease control%

Second and third $eneration TKIs ha"e not been compared headto(head) so e currently selectone or the other based on the side e!!ect pro!ile) mutations pro!ile) dru$ interactions) compliance issues)

and the patients pree0istin$ medical conditions% e do a mutational analysis in patients ho are !ailin$

imatinib or second $eneration TKIs) or those ho pro$ress to A:*':% e do not test baseline mutational

analysis on patients ith nely dia$nosed CM# in C:) as it has not pro"en to predict treatment outcome

either%

Allogeneic stem cell transplantation

The number o! patients under$oin$ alloSCT !or CM#(C: has dropped si$ni!icantly since TKIs

ere introduced) and has more o! an important role hen patients e"ol"e into A:*'C =see belo?%

Doe"er) alloSCT remains an important therapeutic option !or CM#C: in the !olloin$ situations

patients ho !ail at least 7 TKIs and potentially patients harborin$ the T+,-I mutation a!ter a trial o!

ponatinib therapy 5138%

TREATMENT RATION AN ISCONTINATION

The Stop Imatinib =STIM? trial sou$ht to in"esti$ate the ris& o! relapse in patients on imatinib

ith on$oin$ CMR !or


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patients remained sensiti"e to imatinib or a second $eneration TKI upon rechallen$e% It has also been

noted in this study and others that patients ith lo le"el positi"ity !or 'CR(A'# transcripts may be able

to remain o!! therapy ith only close monitorin$% This as recently addressed systematically by French

in"esti$ators) here it appeared sa!e and e!!ecti"e to only resume patients on TKI therapy i! their

transcript le"el became


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since) ith e!!ecti"e TKI therapy) and !ull treatment penetration orldide =to ,334 o! all dia$nosed

patients and continuation o! TKI therapy ithout interruptions? the pre"alence o! CM# ould increase

annually and plateau at around 73+3 to 73;3 at a rate +- times the incidence% This !i$ure is estimated to

be close to ,B3)333 patients ith CM# in the S and about + million patients orldide% This may

represent a considerable burden on patients and the healthcare systems in relation to dru$ a"ailability)

compliance) potential de"elopment o! lon$(term side e!!ects) and costs% There!ore) it is critical to continueresearch into therapies that increase the rates o! durable CMRs% This may be achie"able ith the current

more potent ne $eneration TKIs alone) or in combination ith other a"ailable =pe$(inter!eron alpha(7)

omaceta0ine) and decitabine? or in"esti$ational therapies =LAK7 inhibitors) hed$eho$ inhibitors) stem cell

poisons) and "accines?% Such strate$ies may impro"e the eradication o! minimal residual disease)

potentially ob"iatin$ the need !or inde!inite therapy ith TKIs% Further understandin$ o! the

pathophysiolo$ic e"ents donstream o! 'CR(A'# may help in the de"elopment o! ne strate$ies to

tar$et them%

management of tki resistance

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