MDACC has, for the first time, given their experience of TKI* p3 X' V# D, q e4 A0 c9 G/ c* ~) ?
discontinuation. The doctors at MDACC look at 26 patients who; ?5 S0 ]; k/ {0 X9 {% A( Q: X ~
discontinued therapy from 2003-2012 for various reasons. These reasons
3 d' X% L- D+ t9 V. Oinclude long time in CMR, adverse side-effects, pregnancy and financial; w) p: p- B* \3 ~1 }7 T
constraints. Please note that 17 patients discontinued therapy in CMR
. F7 I8 H4 l/ ~0 P- L: d3 nand the rest in MMR. Of the patients in CMR who discontinued therapy," q, A2 G% S+ L+ N! `. _; D
47% had molecular relapse. Those in CMR who discontinued and had taken; G! {# Y" X) K) l8 ~# A
prior Interferon to a TKI, 50% relapsed. Also note that of these 26" i1 S$ H) H, i; Q$ ?+ @0 _
patients, most had been treated with high dose Gleevec.9 H+ P/ F& g% e9 ~6 l- |; L9 B m
7 x/ J! a4 U% o6 p
"All patients discontinued therapy in CML-CP, all in CCyR, of them, 17) @1 @" Y/ _ B8 p0 ]* F- w9 L
(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR.( C8 J- y4 n5 \) C) s! w, R$ J
The median duration of CMR before TKI cessation was 62 mos, (0- 118).3 m) b. i( W; B; k
The median duration of total TKI therapy was 101 mos (3- 135)."' H: L" w: p6 K6 x6 Z0 [
, Y1 M2 I# S# GTherefore, the median time in CMR before discontinuation was about 5
) c- t! e) D4 B- p; tyears. The median follow-up is only 11 months. The median time for4 k5 v# ?; b/ y! H S" P, h7 @* P
molecular relapse of 8 patients who had been in CMR was 4 months and5 |* p0 v& H+ F- C* u/ h$ u) D
they relapsed with median PCR value of 0.01 on the International Scale.! f) ~* V" x( D; U
; }, K- W; O% ^0 C( _3 q0 I
Of the 7 patients who discontinued when in MMR, 4 remained in MMR at a! F" M# L/ o2 ^' | l& I) o) x0 }5 u" N: z
median follow-up of 21 months, 1 remained in CCR, 1 in active disease/ ~; g8 D2 O) p! Q; A1 q7 o! i) v
and 1 transformed to accelerated phase off drugs. Therefore, from this
5 B7 |$ [' P6 P) a4 |data, scarce as it is, there is a risk of transformation to advanced
7 [" v% Z9 K% ~" y* ~disease if one discontinues drugs in MMR.
6 `$ c' V) d1 b; R, Q
9 c4 n+ F5 ~6 O* E' j3 o7 {2 patients were PCRU (4.5 log machine) and these patients relapsed# a8 D( Z/ Z( C% J; U2 J- d, d$ m
into MMR when drugs were discontinued. v2 M6 A" Y s
. j- m. B9 h) Q! E0 c+ {8 rSeven pts with relapse were treated again with TKI, 3 with nilotinib,3 P2 v8 Q: A* p, G
2 with dasatinib, and one each with imatinib and bosutinib (the latter
5 b C7 T9 S" j$ a1 P8 win AP). After a median of 13 months on therapy (range 4-52) all patients2 L/ Q9 P$ W" o" x) i3 c8 ~7 _, A- G
improved their response, 5 with CMR and 2 MMR (including the pt that had4 f# @6 M* R, J+ t
transformed to AP). They do not say why all patients were not retreated* i0 T2 Q# U8 s
with imatinib and had to take Nilotinib and Dasatinib. Also, note that
8 m$ v& R. R! G, K& l3 yone did not regain CMR at the 13th month mark though it is good news
1 H0 X# h$ L0 R; {6 Y; B4 I0 cthat 5 did. It may take some time to regain CMR for some who have gone
$ o8 I1 F) m, e9 [8 m8 qoff drugs and relapsed. However, from our own list experiences, some
% u: w& Q) X) B9 V# ^0 fhad regained CMR fast when they retook the TKI.8 t/ t8 [: X* G. ^/ e
( z5 d7 C) [; @0 Q6 V- QThe doctors conclude that treatment discontinuation is experimental
- \" ]/ O9 e+ dand cannot be recommended at this stage as a standard procedure.# L2 c, `- H( d9 [
" E5 Y& G; W; q- E, Q5 \
Best Wishes,/ Y! s$ f9 ~& J, y! K9 p6 a" ]7 ^
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Anjana: f7 e7 O$ {+ t$ e, M5 x
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* P1 Y9 M5 q( B5 l3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor6 \$ F, S" [9 E" k: } w. ^; H2 o
Theray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single
' v% |* l1 V6 F: }Institution Experience
! V% P, i$ y- L0 m7 EProgram: Oral and Poster Abstracts* F) M+ }1 E' t. }. R( [' X [
Session: 632. Chronic Myeloid Leukemia - Therapy: Poster III+ A" m/ U8 F, ~ ~2 u
, |3 j" `! w4 I: ]Monday, December 10, 2012, 6:00 PM-8:00 PM4 v) w" \% R J4 P8 k, s+ u4 ~- `
- t% m* X* W" N0 Y0 q2 \# T7 aHall B1-B2, Level 1, Building B (Georgia World Congress Center)# S2 R2 P+ ?4 X" e6 m
" U$ ^5 o a- ~* }: H$ g FOhad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,
5 ?. ?/ R, c/ f/ L( w, gElias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,
8 J( q; e! D. KStefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,
( X0 W, x; \3 kGautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.
( s1 y9 s3 F6 r1 M9 r. fCortes, MD1" U1 {, N) e/ [$ ], w
2 V- E* l6 \# _/ r4 j0 i1 @
1Department of Leukemia, The University of Texas MD Anderson Cancer
) W8 ]: a9 q& Y0 [% m3 GCenter, Houston, TX+ G/ z# R; N. H, K
2Department of Leukemia, The University of Texas M.D. Anderson Cancer$ R6 V5 x& ~/ x' m* x9 d1 S
Center, Houston, TX9 [8 E- v' O4 W( @# `' h L( m" l
! M1 b: ?! B2 F, x8 f5 S
Introduction: Some recent studies have reported on the outcome of CML
: K& C/ C9 X" D4 ppts who discontinued thyrosin kinase inhibitors (TKI) after achieving
/ E2 ?7 {- j4 l* i% s/ hsustained undetectable bcr-abl transcript level. Most patients who stop# X8 I/ n/ N4 z4 m" B; C6 u
TKI have experienced molecular relapse. Most patients respond after
% j8 U& K5 e* }7 \resuming TKIs regaining undetectable bcr-abl transcript levels. These
. d) g0 E8 \$ L+ x' z& Hseries have prospectively planned treatment discontinuation and included0 U) i8 Z2 @# Q9 F. t& x
only pts that have sustained complete molecular response (CMR) for at
' J& m; J$ ]0 _9 eleast 2 yrs. However, in many instances pts may want to discontinue TKIs3 r; ~0 x/ ~2 N
not in CMR. Various reasons may lead patients to discontinue TKI: L4 f- V% }& O! @
treatment unexpectedly, among them severe adverse effects, pregnancy or
. p0 n6 l+ `7 w, K* C" geconomic constraints. This single institution experience reflects the
8 H3 x3 \' \+ g5 ]! Hheterogeneous nature of pt-driven TKI discontinuation.! B* Z8 G8 v3 m/ Z
+ b$ }+ j% t! y" x
Aim: To characterize the outcome and profile of CML pts who chose to
( X& k$ P% [& h ?6 ]4 }discontinue TKI therapy in a single center regardless of their initial% }: P5 M& l- k! j' O% _
response to TKI therapy.
" y) z' d6 D0 S( {( v1 B% t
. p- ?2 H: s7 C' JMethods:We retrospectively analyzed MDACC data on all patients with CML
8 @8 z/ ? ?+ W$ ^that were treated with TKIs in our institution and discontinued therapy.
8 H3 Z* {0 I ]& X
2 }3 o0 F$ \* y0 K0 c- j; [1 O* ]Results: A total of 26 patients with CML-CP managed at MDACC
$ E0 o- \4 X! [1 _1 ldiscontinued TKI between 2003 and 2012. The total median follow up time
; s' ~4 W) c* T8 O2 F) x: ysince diagnosis was more than 120 months (mos) (range, 45 mos to 304
7 |, T5 m6 X$ U3 [0 w( j6 Pmos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were
& d ]: @) ]2 E) sfemale. All pts had been diagnosed and treated in chronic phase.) L4 E) L" |! S1 m% c+ K# E
Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI
$ A5 ?6 i# k. m* x u; Z3 yas initial therapy (4 received imatinib 400mg/day, 10 imatinib
5 _- C4 k0 Q- b; D A8 {600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with
, m3 Z7 ]$ e5 T4 ?; dIFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN6 Y' X6 ]3 k8 s0 z" R3 J
failure. Pts treated frontline with TKI started therapy within a median
, |& p- v: ~8 u* z/ Vof 0.8 mos from diagnosis (range 0 to 4) and those with previous/ [9 U) g% ?* i/ K& q
interferon (n=11) after a median of 60 mos from diagnosis (31 to 164
7 s1 f b0 f. X% R1 h0 E smos). Before TKI discontinuation 21pts (81%) were receiving their first
5 w" t5 O; y6 A6 D }% HTKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete
. {8 Y5 Y- ^7 n& F' P- t+ Acytogenetic response (CCyR) had been achieved in all 26 pts at a median
2 F# [+ r( Q* r4 Vof 3.5 mos (3-93); Major molecular response (MMR) in all at a median of- ?( q# o$ o/ x4 S
9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All& e! S. m- b* C; b6 Z
patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)
& W1 ~' |% A5 B, J1 W$ J* Ehad undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The
4 B" O8 v$ U M2 h Z; \median duration of CMR before TKI cessation was 62 mos, (0- 118). The# ^- l W& W2 @1 \ [1 t
median duration of total TKI therapy was 101 mos (3- 135).
" }9 R7 Z) u0 V( ` v7 i! J
' P/ b2 E8 l8 M+ CFourteen pts (54%) discontinued TKI due to adverse events, 2 pts
/ @; x, l% i( _8 J/ h; p7 T, o. d" fdiscontinued to become pregnant, 5 decided to stop after long CMR, and 5
4 o" _+ @. c/ ]# zpts discontinued for financial reasons. After TKI discontinuation1 y3 f! W* q% h9 T h6 p
patients were followed for a median of 11 mos (5-131). Among pts with
6 [4 b4 k9 z! I( z) ^CMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a4 a! s* H7 y& x" t6 M* i. V
median of 4 mos (1-11) from discontinuation with median transcript level& G+ q+ L5 s; |2 B9 N
at relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF
' y8 w# n* T4 ~1 g' btherapy had CMR at time of TKI discontinuation, 50% of them relapsed.# \' Y7 \( x3 C! A1 |+ |, E
Among 7 pts who discontinued therapy in MMR, after a median follow-up
5 ]& L6 p+ u: H( V: [ @from discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,8 E4 Q. n2 a0 Z2 }) P& L- T
one has minor CyR and one CCyR without retreatment at last follow up
; O2 ]* N0 T8 |; D6 O' u# Vafter 78 and 105 months from TKI discontinuation, and one transformed to& K; |/ I' Z- h7 A0 ?, F
accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed2 D! M% f& U( D5 C$ U
to MMR. Three pts had a transient molecular recurrence with spontaneous7 V+ h6 E5 o# u
re-gain of CMR. Seven pts with relapse were treated again with TKI, 3" D6 V) y6 z$ E
with nilotinib, 2 with dasatinib, and one each with imatinib and
8 S5 D F5 Z' Cbosutinib (the later in AP). After a median of 13 months on therapy- N. |5 G+ Y0 z$ K8 l
(range 4-52) all patients improved their response, 5 with CMR and 2 MMR8 s( Z6 W6 N8 }9 `. V& a8 E
(including the pt that had transformed to AP). There were no deaths or/ d* H3 o5 [' l+ D S+ h
transformations to blastic phase of CML. At last follow up 14 (54%) pts
& c) U3 N1 F! j. n' V* P M* @2 Z/ |were in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and
) P4 ~/ o0 p! APCyR.
1 B1 S7 \3 R+ z- _$ _
+ n; [7 E9 M& RConclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular
* W2 ]& W3 w- [# B+ a0 `relapse in nearly half of the pts who discontinue therapy in CMR. Some! ^0 Q, e% C& E- Y' @4 L; S
pts who discontinue in MMR may have sustained MMR. Treatment/ f" b9 r+ A, q/ U9 U8 i
discontinuation should be considered experimental and cannot be& L7 m# B6 W: O8 ?; r
recommended to pts as a standard approach.
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8 `- }/ r) J, i, T4 u0 DDisclosures: Ravandi: BMS: Honoraria, Research Funding. |