MDACC has, for the first time, given their experience of TKI
6 u1 _1 I& }/ }1 D! x) vdiscontinuation. The doctors at MDACC look at 26 patients who
0 j3 f# E! X5 I; D- tdiscontinued therapy from 2003-2012 for various reasons. These reasons
& X7 c5 x* T2 O3 minclude long time in CMR, adverse side-effects, pregnancy and financial
3 r% O. ]( u- {2 c3 q. G4 K( Zconstraints. Please note that 17 patients discontinued therapy in CMR
0 ~* F; Y) M0 C1 iand the rest in MMR. Of the patients in CMR who discontinued therapy,
4 c, R* s( @+ @0 k' S+ m; h47% had molecular relapse. Those in CMR who discontinued and had taken
9 ], y8 L4 X `2 d2 Q4 kprior Interferon to a TKI, 50% relapsed. Also note that of these 26
+ _3 [0 @5 m' _/ A0 T5 l: Y& Kpatients, most had been treated with high dose Gleevec.3 E& Z, ^+ X( l+ {$ o* p+ z3 t$ }
7 k- A% o, f3 a2 b! i" u: J"All patients discontinued therapy in CML-CP, all in CCyR, of them, 17
4 P3 c- i: U! {: G% ~(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR.9 c1 `3 z" y8 i7 h
The median duration of CMR before TKI cessation was 62 mos, (0- 118).. d# U1 F; S9 m, \+ u% h3 V
The median duration of total TKI therapy was 101 mos (3- 135)."
( c* K' b y& g
) E! `# L* h/ w# pTherefore, the median time in CMR before discontinuation was about 5
8 ~7 g$ ~, K2 N4 P9 Z0 L J- Fyears. The median follow-up is only 11 months. The median time for' F2 y* B. d8 z- ]. m! S# O1 `! V
molecular relapse of 8 patients who had been in CMR was 4 months and6 s9 p: J+ [' m2 S9 a& V
they relapsed with median PCR value of 0.01 on the International Scale.1 a D" A. w! a& j4 L
. z' `0 r& q' e9 oOf the 7 patients who discontinued when in MMR, 4 remained in MMR at a( p4 k$ ^' w+ L) a
median follow-up of 21 months, 1 remained in CCR, 1 in active disease8 g- {( }0 E- e+ ]
and 1 transformed to accelerated phase off drugs. Therefore, from this
5 C$ D4 j1 X$ k! r) F& A/ ^+ G! Hdata, scarce as it is, there is a risk of transformation to advanced
* I6 ~9 S" t* ~: `: m$ z N* Pdisease if one discontinues drugs in MMR.2 [" P, [- {) a7 H+ g& h
% C7 h. k9 d4 x- S3 O2 patients were PCRU (4.5 log machine) and these patients relapsed
) k6 C" N5 k! F" |. n8 }" h# I* Ginto MMR when drugs were discontinued.
8 z% f* e$ `1 N# G+ ]9 M+ ~7 f( @0 Y, z0 w. a) v) E
Seven pts with relapse were treated again with TKI, 3 with nilotinib,8 q6 ]+ O* D3 U% N. C. D
2 with dasatinib, and one each with imatinib and bosutinib (the latter
3 L0 \0 s+ ] r* R" k G: ]( xin AP). After a median of 13 months on therapy (range 4-52) all patients
b$ l9 e" h; N8 b1 i+ t6 cimproved their response, 5 with CMR and 2 MMR (including the pt that had
$ v ?9 Q N- [' p* E: h( b& itransformed to AP). They do not say why all patients were not retreated
* f3 P. r7 k: Gwith imatinib and had to take Nilotinib and Dasatinib. Also, note that
9 \ L! B8 a2 F0 [one did not regain CMR at the 13th month mark though it is good news
7 Z9 j3 N3 Z* Q# nthat 5 did. It may take some time to regain CMR for some who have gone
, Y( g ?% v( r! joff drugs and relapsed. However, from our own list experiences, some
" q" W& l$ U' zhad regained CMR fast when they retook the TKI.* E/ U- S+ P2 U2 Z
- L1 l( x+ F$ }2 p- \
The doctors conclude that treatment discontinuation is experimental t7 }7 _6 x a. ~: e8 ^( r0 J
and cannot be recommended at this stage as a standard procedure.
; F" r A; M7 X2 _% z
4 N. ~" S5 p2 t& z R6 \9 `* tBest Wishes,. G8 d5 T' o+ }$ w+ ^* I( d9 F
0 A+ C% o3 n z9 c
Anjana+ u7 D/ w) h: u' r: K
7 X# h& _# }$ p
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F( K7 q1 v* z+ Q$ q/ k
& |1 f/ A: ^9 I t2 @4 l+ ]& k* [' P) F* x$ x/ G# ]
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" ^! \2 T; U) U5 A
' Y9 q6 T7 b( L8 Z& Y& U3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor
2 C0 |7 M* G+ [+ d% LTheray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single5 B& Z8 j3 U! ?9 M7 |, Y
Institution Experience
8 g# C; k! u# \; e/ S/ `& {Program: Oral and Poster Abstracts
2 I0 b- N6 V& V+ u |Session: 632. Chronic Myeloid Leukemia - Therapy: Poster III! P0 a' e3 {* [9 e+ E
6 z! \& M, E- e* l; L. h! c; _
Monday, December 10, 2012, 6:00 PM-8:00 PM
( u3 |: [2 s) J5 X6 V h
: X2 h3 `4 S+ Q! sHall B1-B2, Level 1, Building B (Georgia World Congress Center)
, N2 ]/ [! M4 Q( ~
+ a' D6 w0 h5 q5 P" ?Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,
! [% P* j6 a) R9 z' t* @- UElias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,
0 _- u6 d: ^) t# R/ B4 O& T5 ~" dStefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,. z# p* N( w# I- ~2 Z! m' g7 {, u
Gautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.$ Q) F9 D+ A' _1 `( a- A
Cortes, MD1 J0 C( f- s/ }$ D( X% Z
& g: U5 j( I& ?. {3 t
1Department of Leukemia, The University of Texas MD Anderson Cancer
0 q8 }* ?8 o6 k/ rCenter, Houston, TX; ]7 j1 z" u& a: q- t( `. r
2Department of Leukemia, The University of Texas M.D. Anderson Cancer
" @- T @5 q7 B y, vCenter, Houston, TX
6 ?6 ^- e5 D( x( g+ k
' A) L9 W6 s; ?# c" z& w: c6 G! @Introduction: Some recent studies have reported on the outcome of CML" v& \( V- m. e8 K$ U h; C% `
pts who discontinued thyrosin kinase inhibitors (TKI) after achieving3 v' C& c. K8 O9 B m& I8 Y
sustained undetectable bcr-abl transcript level. Most patients who stop5 U( V, P9 y u
TKI have experienced molecular relapse. Most patients respond after
O* r! A, _; e M7 P, i z7 Kresuming TKIs regaining undetectable bcr-abl transcript levels. These% x G* \! U: q+ I
series have prospectively planned treatment discontinuation and included
8 _* _7 A2 Y/ X' x- Q) b" d! bonly pts that have sustained complete molecular response (CMR) for at' T K, z& p0 Z# J
least 2 yrs. However, in many instances pts may want to discontinue TKIs, _6 v2 T1 b8 m8 [6 @0 X
not in CMR. Various reasons may lead patients to discontinue TKI0 _3 ~9 [/ I# e# t5 [
treatment unexpectedly, among them severe adverse effects, pregnancy or; M3 f& `( v. ]- I
economic constraints. This single institution experience reflects the ~ I- j- u* ?5 m& D
heterogeneous nature of pt-driven TKI discontinuation.+ Y+ E+ b4 p! H8 Y. f9 \, s
# p) }$ O9 p) E2 ?6 y k
Aim: To characterize the outcome and profile of CML pts who chose to
% S, n6 e2 W- |1 pdiscontinue TKI therapy in a single center regardless of their initial. c7 u% \7 @9 b5 X! R- x& h6 m3 a
response to TKI therapy.- P! F' q+ _& H+ @( T
3 w7 W, g4 P% N" d. y2 H2 J
Methods:We retrospectively analyzed MDACC data on all patients with CML
4 Z4 r; p( n0 n4 Y2 S; U$ \/ E* }that were treated with TKIs in our institution and discontinued therapy.
0 ~5 } q+ h4 q8 m% u5 S; t
8 n1 k* A- ^' V+ I# `Results: A total of 26 patients with CML-CP managed at MDACC1 s2 u% p/ K2 a3 {' ~
discontinued TKI between 2003 and 2012. The total median follow up time+ D' k7 o: v0 u
since diagnosis was more than 120 months (mos) (range, 45 mos to 304! b2 X& j( p" G* M; Q( R! Y
mos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were
( m e& Z4 |7 rfemale. All pts had been diagnosed and treated in chronic phase.# Y" |, e) J. O e% K8 E2 o
Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI
3 L9 b: z& C9 l, _. q( }% Has initial therapy (4 received imatinib 400mg/day, 10 imatinib
* l6 H% Y, R$ M/ W% v600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with
. I! C: z4 J- \/ W. t8 `IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN3 l; G) u+ T; H# G: I3 K
failure. Pts treated frontline with TKI started therapy within a median
, G! B3 m2 f G3 i: p8 B1 Xof 0.8 mos from diagnosis (range 0 to 4) and those with previous4 p# S0 g1 q2 C& Z* U7 P2 r
interferon (n=11) after a median of 60 mos from diagnosis (31 to 164* o* X2 s' I* @* q! y7 L
mos). Before TKI discontinuation 21pts (81%) were receiving their first
: s1 y3 K" W5 `! z4 zTKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete, X+ B& v' L! ?- E: ^ |7 ]
cytogenetic response (CCyR) had been achieved in all 26 pts at a median
) ~6 E% h; Z) Fof 3.5 mos (3-93); Major molecular response (MMR) in all at a median of# B/ m1 s9 \* M2 [
9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All6 R- Q5 S# o: I; w9 V2 g' T6 Z
patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)
- t0 A, q' Q+ @2 E3 ~+ Lhad undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The
. H8 R9 q6 O/ t3 Umedian duration of CMR before TKI cessation was 62 mos, (0- 118). The
) y w) F) y* Z! h3 xmedian duration of total TKI therapy was 101 mos (3- 135).
% B" p3 f7 \; e0 b- W5 l5 d0 Q5 t' D1 L1 B3 G# K N: i9 v9 [
Fourteen pts (54%) discontinued TKI due to adverse events, 2 pts
0 a2 Q% H7 x7 ~/ Rdiscontinued to become pregnant, 5 decided to stop after long CMR, and 58 U9 b" e3 H$ L1 i! j/ X0 A! g0 Q
pts discontinued for financial reasons. After TKI discontinuation
P3 o5 k# Q! U8 k8 D+ }patients were followed for a median of 11 mos (5-131). Among pts with
% V p- V* H6 C% F- I2 WCMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a& H( X& ?+ U6 A v* \- r
median of 4 mos (1-11) from discontinuation with median transcript level R! \, ]6 Z) Y. H: T
at relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF6 _% s! H, c/ H, c4 w
therapy had CMR at time of TKI discontinuation, 50% of them relapsed.: ^5 L' J. U0 E: G6 i
Among 7 pts who discontinued therapy in MMR, after a median follow-up- @0 {& F2 f; e( l7 v' s: s- _8 g+ H
from discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,0 M4 D* g) }& X8 b( P
one has minor CyR and one CCyR without retreatment at last follow up
* x1 E" x4 r8 m9 Y( E$ Vafter 78 and 105 months from TKI discontinuation, and one transformed to. a& ^1 A4 T4 V8 s( J( ~. f3 L+ a
accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed
0 _) Z k9 ]& L. ^" O, j4 w+ }to MMR. Three pts had a transient molecular recurrence with spontaneous$ v; h4 r b" E; {6 g
re-gain of CMR. Seven pts with relapse were treated again with TKI, 3
' W! k: A' \& W0 nwith nilotinib, 2 with dasatinib, and one each with imatinib and% }4 H0 \0 I& h3 i; k+ N
bosutinib (the later in AP). After a median of 13 months on therapy' y# W$ }+ s/ j6 L, `3 h
(range 4-52) all patients improved their response, 5 with CMR and 2 MMR! d4 l4 V7 y3 C v8 K+ {* K4 F- g
(including the pt that had transformed to AP). There were no deaths or7 z( ~" q7 w* s
transformations to blastic phase of CML. At last follow up 14 (54%) pts
- R* J$ Z; l: z/ f- Pwere in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and
% q0 p" \2 S2 UPCyR.
& U# m' y$ b6 Z; `3 E
9 A2 {. J9 e% P) p( `Conclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular
, i9 H2 y. R' P1 j" `relapse in nearly half of the pts who discontinue therapy in CMR. Some @% T [$ e" ]2 g- |1 t8 t; O
pts who discontinue in MMR may have sustained MMR. Treatment5 m, t+ O b; Q
discontinuation should be considered experimental and cannot be( o8 G6 Z/ ^7 o' M
recommended to pts as a standard approach.
8 Q3 }. e: t' O6 O7 w
; X8 X; X) ~0 J( t6 bDisclosures: Ravandi: BMS: Honoraria, Research Funding. |