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Any BCR-ABL Reduction Below10% at 6 Months of TherapySinificantly !"pro#es $utco"efor CML atients with a oor

Response at & Months

Branford S et al'

Proc ASH 2013;Abstract 254.

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Bac(round

The molecular response at 3 months after commencementof tyrosine kinase inhibitor (TK! therapy for patients "ith#$% has pro&nostic si&nificance.

Analyses by 'eelakantan et al su&&est that aitional

measurement of )#*+A)%1 transcript le,els at - monthsas little pro&nostic ,alue to the 3+month result (Blood2013;1212/3!.

o"e,er another recent stuy base on cyto&eneticresponse conclue that for patients "ith poor response at

3 months assessin& the response at - months maypro,ie a better preictor of lon&+term outcome(Haematologica2013;1--!.

Study o)*ecti#e+ To e,aluate the pro&nostic importanceof assessin& both the 3+ an -+month molecular response

for patients "ith chronic+phase #$% (#$%+#!.)ranfor et al. Proc ASH 2013;Abstract 254.

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Study ,esin

The stuy inclue patients "ith #$%+# enrolle inconsecuti,e clinical trials of first+line imatinib from 2000 to2011 (n 6 52!.

7 $any patients "ere treate before alternati,e TKs "erea,ailable but s"itche therapy.8

The utility of )#*+A)% as a preictor of eath (o,erallsur,i,al! pro&ression (A9)# pro&ression+free sur,i,al!treatment failure (failure+free sur,i,al! an ma:or molecularresponse ($$*! "as assesse.

atients "ere i,ie accorin& to the 2013 uropean

%eukemia'et (%'! efinitions of 3+ an -+month molecularresponse

7 3 mo optimal 10=

)ranfor et al. Proc ASH 2013;Abstract 254.

8tuy "as not po"ere to assess the effect of treatment inter,ention

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$utco"es at .ears for atients inthe $pti"al /10% #ersus 2arnin

/310% Cateory at & Months

)ranfor et al. Proc ASH 2013;Abstract 254.

$utco"e at y

$pti"al

/n 4 06

2arnin

/n 4 100 p-#alue

@,erall sur,i,al /= = 0.0003

ro&ression+free sur,i,al = -= ?0.0001

ailure+free sur,i,al 3= 4-= ?0.0001

$$* = 42= ?0.0001

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Sur#i#al of atients in the&-Month 2arnin Cateory 5rouped

)y Cateory at 6 Months

Bith permission from )ranfor et al. Proc ASH 2013;Abstract 254.

$#erall Sur#i#al /n 4 7

@ptimal 100=Barnin& 100=

ailure /1=

.ears after i"atini) start

0 1 2 3 4

ro)a)ility%

0

20

40

-0

0

100

P6 0.001

ailure /2=

.ears after i"atini) start

0 1 2 3 4

ro)a)ility%

0

20

40

-0

0

100

P6 0.02

@ptimal 100=Barnin& 4=

roression-8ree Sur#i#al /n 4 7

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MMR for atients in the &-Month2arnin Cateory 5rouped )y Cateory

at 6 Months

atients in the "arnin& cate&ory at 3 months "ho ha,e )#*+A)%1 ?10= at - monthsha,e impro,e outcomes

'o si&nificant ifference in any outcome assessment after - months bet"een those"ho "ere in the optimal cate&ory at 3 months an - months ,ersus those in the"arnin& cate&ory at 3 months "ho mo,e to the optimal cate&ory at - months

Bith permission from )ranfor et al. Proc ASH 2013;Abstract 254.

P6 0.001

ailure 3=

.ears after i"atini) start

0 1 2 3 4Cu"ulati#e

incidence%

0

20

40

-0

0

100

P? 0.0001

Barnin& -5=

@ptimal =

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3

10

0 months

atients at 9ih $noinRis( of oor Response

#han&e of )#*+A)%1 le,el from baseline to 3 months "as important foroutcome

Bith permission from )ranfor et al. Proc ASH 2013;Abstract 254.

tanarise)aseline 100

BCR-ABL1

% !S

n 4 100

54=no failure

42=$$*

2arnin

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:se of 9al#in Ti"e to redict$utco"e for atients at 9ih $noin

Ris( of oor Response

Bith permission from )ranfor et al. Proc ASH 2013;Abstract 254.

Bhen )#*+A)%1 "as measure as a continuous co,ariate patients "ith the same,alue at 3 months ha better outcomes if their baseline ,alue "as hi&her.

&

10

0 "onths

n 4 ;7al,in& Time0 ays

meian 32 ays(ran&e 1-+0!

*ate of reuction "asmeasure by the numberof ays o,er "hich

)#*+A)%1 hal,e9al#in Ti"e

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$utco"es for atients in the2arnin Cateory at & Months )y

9al#in Ti"e Responses

)ranfor et al. Proc ASH 2013;Abstract 254.

$utco"e at y

$#erall

/n 4 100

9al#in ti"e response

70 d

/n 4 ;7

370 d

/n 4 17 p-#alue

@,erall sur,i,al = 3= -= 0.000

ro&ression+free

sur,i,al-= 0= -= 0.01/

ailure+free sur,i,al 4-= 5-= /= ?0.0001

$$* 42= 53= 5= 0.01/

The hal,in& time at 3 months may also be preicti,e of o,erall anpro&ression+free sur,i,al for the 35 patients "ho subseCuently met the %'failure criteria at - months.

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Author Conclusions

)ranfor et al. Proc ASH 2013;Abstract 254.

)#*+A)%1 >10= at 3 months is a poor risk cate&ory.

'ot all patients "ith a )#*+A)%1 ,alue >10= at 3

months ha,e a hi&h on&oin& risk of treatment failure.

7 Any reuction belo" 10= by - months may impro,e

outcome.

7 The rate of reuction o,er the first 3 months is an

important factor for outcome an coul be consiere

"hen makin& therapeutic ecisions.

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!n#estiator Co""entary+ BCR-ABL Le#els 10= at 3 months.

$y recommenation is not to chan&e treatment for any patient at 3months but to ensure that the patients are monitore at - months. "oul consier chan&in& the treatment for those "ho continue torespon poorly.

Bith imatinib about a thir of patients onDt achie,e a &oo response at

3 months an about half of these patients "ill continue to fare poorly at- months. o"e,er "ith asatinib or nilotinib only 10= to 15= ofpatients "ill not ha,e a &oo response at 3 months an half of those"ill continue to respon poorly at - months. That is a rationale for usin&asatinib or nilotinib as up+front therapy.

Interview with Jorge E Cortes, MD, January 24, 2014