MDACC has, for the first time, given their experience of TKI0 h* s' \% J5 N* t- p3 A
discontinuation. The doctors at MDACC look at 26 patients who
' U9 H+ c% l" }& P4 Xdiscontinued therapy from 2003-2012 for various reasons. These reasons' `7 F3 k, w/ @
include long time in CMR, adverse side-effects, pregnancy and financial0 _ Q/ F: t1 s, F( w
constraints. Please note that 17 patients discontinued therapy in CMR. f/ J7 Q2 o) I8 \
and the rest in MMR. Of the patients in CMR who discontinued therapy,- w( G: }# u5 ]& w& }
47% had molecular relapse. Those in CMR who discontinued and had taken" O, c: S5 l9 X3 {, E5 @) v
prior Interferon to a TKI, 50% relapsed. Also note that of these 26
8 E" g, N; u/ Ypatients, most had been treated with high dose Gleevec. `4 {5 ]( G X
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"All patients discontinued therapy in CML-CP, all in CCyR, of them, 170 c' F: }1 O7 \0 M
(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR.
% E, ?$ f# B& Q6 KThe median duration of CMR before TKI cessation was 62 mos, (0- 118).
- C2 x4 t6 M1 yThe median duration of total TKI therapy was 101 mos (3- 135)."' v0 u& ^9 y) o/ Q9 E' Z
" Z! v9 ]& b3 g3 U FTherefore, the median time in CMR before discontinuation was about 5
, J/ f' M, W7 X- ~9 q2 w% Hyears. The median follow-up is only 11 months. The median time for. X3 N$ v6 r+ ~) `9 |
molecular relapse of 8 patients who had been in CMR was 4 months and) v) E; q* h& ^) H
they relapsed with median PCR value of 0.01 on the International Scale.
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Of the 7 patients who discontinued when in MMR, 4 remained in MMR at a
- C0 b# {2 ]4 K$ y3 h6 ^ wmedian follow-up of 21 months, 1 remained in CCR, 1 in active disease
/ ]1 I$ C! `) [9 t% N( G% }and 1 transformed to accelerated phase off drugs. Therefore, from this& i0 t" ?: @' T. d
data, scarce as it is, there is a risk of transformation to advanced5 i8 O. A D$ V: M5 |; A W* P5 R. E4 @
disease if one discontinues drugs in MMR.
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2 patients were PCRU (4.5 log machine) and these patients relapsed% r/ Z( v* Q. q4 N) w: D
into MMR when drugs were discontinued.
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( B. M, r! H- ~( u6 A% NSeven pts with relapse were treated again with TKI, 3 with nilotinib,
8 i( v6 Q; p- I! _2 with dasatinib, and one each with imatinib and bosutinib (the latter
3 f3 o; V' t3 G- c* z1 o1 Bin AP). After a median of 13 months on therapy (range 4-52) all patients
# `+ X: s) \. m* E- k9 e, ~& ^8 ~+ H4 Uimproved their response, 5 with CMR and 2 MMR (including the pt that had+ _# h+ Q$ B# F9 w7 p
transformed to AP). They do not say why all patients were not retreated
7 P6 V6 p! o; G7 K1 ]with imatinib and had to take Nilotinib and Dasatinib. Also, note that
" o c8 e2 q7 B- Yone did not regain CMR at the 13th month mark though it is good news
+ k, T) u. P# v) nthat 5 did. It may take some time to regain CMR for some who have gone$ F t! u) W4 h9 _
off drugs and relapsed. However, from our own list experiences, some
]5 U, f) {2 N- _& ]% |! ~had regained CMR fast when they retook the TKI.
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The doctors conclude that treatment discontinuation is experimental
& O6 G" R8 F O& r, Aand cannot be recommended at this stage as a standard procedure.
9 w! D* h. N8 j3 O+ C; x' l2 [+ n) l' h% w" J( M" _
Best Wishes,
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Anjana
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; }2 ~( Z7 \& [* B! j$ I1 ~
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+ q% B/ P" Y- |4 J3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor9 ?; g/ P3 P( n, o# c7 r
Theray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single
$ n9 R- A8 a M6 `, d( YInstitution Experience5 s8 {2 i3 b, M' u0 @5 ~1 E
Program: Oral and Poster Abstracts' x% ^6 N0 m J$ A# B
Session: 632. Chronic Myeloid Leukemia - Therapy: Poster III
& B. z% e3 x k; X8 H: ~3 n
* s2 X* H% i0 x9 \8 KMonday, December 10, 2012, 6:00 PM-8:00 PM
, e3 h. q5 S8 }7 X# W1 ]3 n# D% o5 P0 O' R# _
Hall B1-B2, Level 1, Building B (Georgia World Congress Center)
: r4 a! P* [8 T2 K9 q0 t, ?/ T0 R* B, e9 K/ y8 E( c
Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,
/ r! `1 n5 k. A+ w: P4 O! CElias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,
$ _- o7 R6 ]$ g2 Y& ^( Z, wStefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,
; O7 O0 {2 Y$ w6 |2 e+ ] R7 E' CGautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.7 n+ h9 S) J! u) R+ ~0 q a1 q2 Y
Cortes, MD1! O7 v) G$ u( \4 Y( q2 t n( N- x
8 e0 }3 e% ~ ~: k, o
1Department of Leukemia, The University of Texas MD Anderson Cancer
" a2 E6 a. M. ^: F; k4 wCenter, Houston, TX0 A' L5 w0 f4 [
2Department of Leukemia, The University of Texas M.D. Anderson Cancer3 f. \6 d) |6 `
Center, Houston, TX
: D3 N; V& c8 R1 a4 W k6 T5 e
, m2 l# ?; J; o" u( U, k3 gIntroduction: Some recent studies have reported on the outcome of CML+ `; }# f6 n U0 J" J" g
pts who discontinued thyrosin kinase inhibitors (TKI) after achieving
8 B/ Y; m N! [' p5 c4 Jsustained undetectable bcr-abl transcript level. Most patients who stop
# l8 R0 g5 K7 JTKI have experienced molecular relapse. Most patients respond after. W% T$ h3 b: @. g$ ?7 y$ @
resuming TKIs regaining undetectable bcr-abl transcript levels. These1 I1 ~0 D7 F5 T7 p$ `# P3 ]7 p0 }
series have prospectively planned treatment discontinuation and included
1 f+ p9 [0 F- a$ T( n. xonly pts that have sustained complete molecular response (CMR) for at
1 p6 r3 s2 E$ ~& A! F$ Ileast 2 yrs. However, in many instances pts may want to discontinue TKIs% u- v9 ^* M& b
not in CMR. Various reasons may lead patients to discontinue TKI
& c* n2 \. f" ]2 _/ atreatment unexpectedly, among them severe adverse effects, pregnancy or
5 T& i" X! i Ieconomic constraints. This single institution experience reflects the
" N' C: i# s( O4 U4 oheterogeneous nature of pt-driven TKI discontinuation.
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1 c* w& a' ^( y" Z; ?) v" \Aim: To characterize the outcome and profile of CML pts who chose to* T: `! v, |% V: O1 O' ]
discontinue TKI therapy in a single center regardless of their initial
3 {+ _6 k$ H7 M9 ~$ i$ vresponse to TKI therapy.# m N4 K/ u% o( S
( F0 v0 V: _; }5 V& Z `Methods:We retrospectively analyzed MDACC data on all patients with CML
# ]1 D% N* h7 z) x0 |. [9 Cthat were treated with TKIs in our institution and discontinued therapy., p/ p, H, @7 p! a" \" @
! ~2 H0 d$ o5 H0 v! v) a
Results: A total of 26 patients with CML-CP managed at MDACC3 G5 ]$ E) x; }8 g, K1 P
discontinued TKI between 2003 and 2012. The total median follow up time
* @1 s( k3 B- x4 Psince diagnosis was more than 120 months (mos) (range, 45 mos to 304
" d' ~9 p# \. Q) H, M: v5 s, `mos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were+ N" x- C: S! U4 H8 _
female. All pts had been diagnosed and treated in chronic phase.
+ k4 r( J' }1 \0 O2 LInterferon was initial therapy in 11 pts (42%) and 15 pts received TKI! i F; ^/ L1 R
as initial therapy (4 received imatinib 400mg/day, 10 imatinib
4 B- X* a4 J3 A5 e) n/ E600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with6 n0 x/ Q4 H, y0 e- V) \- m9 n8 E2 z
IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN( o) O/ u/ Z. V3 R' C, N# `
failure. Pts treated frontline with TKI started therapy within a median# ?9 T+ l* E V! m, M
of 0.8 mos from diagnosis (range 0 to 4) and those with previous. i% c2 c7 e4 a0 D* F/ ^( z/ O7 k
interferon (n=11) after a median of 60 mos from diagnosis (31 to 1641 ^% ]: t9 R+ ~5 k, o
mos). Before TKI discontinuation 21pts (81%) were receiving their first
7 z( ^8 L8 ~ L t. z% FTKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete$ O, I0 t" H9 u; g# l9 R Y
cytogenetic response (CCyR) had been achieved in all 26 pts at a median
( q1 }' D' r$ F( E- c( c4 P' Pof 3.5 mos (3-93); Major molecular response (MMR) in all at a median of1 l( K( I+ D# }# R% a# P
9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All9 h& n8 k: U, o) P& B
patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)
& z N* w8 m$ Ghad undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The3 O M3 H! W1 B- w& X) @
median duration of CMR before TKI cessation was 62 mos, (0- 118). The9 s+ S# X5 t# B
median duration of total TKI therapy was 101 mos (3- 135).
9 u4 a' C& n0 H$ e$ e0 y* U" f3 H1 S
Fourteen pts (54%) discontinued TKI due to adverse events, 2 pts9 _! U9 A. V2 z+ O" w, H
discontinued to become pregnant, 5 decided to stop after long CMR, and 58 w+ k4 H! a; v: D% u; ^/ T0 X7 G
pts discontinued for financial reasons. After TKI discontinuation
( C2 \/ V C' apatients were followed for a median of 11 mos (5-131). Among pts with* B4 i9 {% W$ Q7 Z) s% X
CMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a
; l* o, b% Z: _. T) [median of 4 mos (1-11) from discontinuation with median transcript level+ J& P3 S% W3 E; z/ ~( j( B# J# m j
at relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF s4 u a7 B- Q6 u8 L1 ]* l( j
therapy had CMR at time of TKI discontinuation, 50% of them relapsed.
3 G" b5 k/ F4 j3 X, J1 vAmong 7 pts who discontinued therapy in MMR, after a median follow-up
9 f6 ^& P! f. c _: L$ M! vfrom discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,* d; u+ D. K7 r8 j3 t$ B9 W
one has minor CyR and one CCyR without retreatment at last follow up
: S9 B# s4 p- m: u; ?after 78 and 105 months from TKI discontinuation, and one transformed to; M+ N( w( l, n8 r' Q/ u3 n6 i
accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed
4 j) w" o, x3 n; z3 N; [2 q, K( dto MMR. Three pts had a transient molecular recurrence with spontaneous
! f5 Y: J$ S; D$ d" O$ L7 Ere-gain of CMR. Seven pts with relapse were treated again with TKI, 3: K0 A, R& Z4 z" A# K
with nilotinib, 2 with dasatinib, and one each with imatinib and% c) {* ?1 d6 Q, N5 _( A4 u' J
bosutinib (the later in AP). After a median of 13 months on therapy
8 o _0 N \. F: O! p1 \3 T; Z" H9 q" S(range 4-52) all patients improved their response, 5 with CMR and 2 MMR4 a* m, n* p6 _7 L( P
(including the pt that had transformed to AP). There were no deaths or$ x6 m# N- r/ e1 S! P
transformations to blastic phase of CML. At last follow up 14 (54%) pts
% X! ]1 B1 e: s& I5 U( c2 _were in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and
0 c. A+ {3 V9 V$ Q& t& [PCyR.2 e9 e4 u/ ^0 @4 [ y
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Conclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular
/ R" B0 d4 Y7 k% ]' X4 @0 P# t8 rrelapse in nearly half of the pts who discontinue therapy in CMR. Some
- E$ @ \0 t; z. g( cpts who discontinue in MMR may have sustained MMR. Treatment$ w8 ~4 X& ~ _, X v
discontinuation should be considered experimental and cannot be
7 P0 q/ w1 \9 S/ S- a1 u7 X& lrecommended to pts as a standard approach./ j; @4 R/ J, X9 p
: a# ^2 x4 B" W7 g' t/ Q7 ODisclosures: Ravandi: BMS: Honoraria, Research Funding. |