MDACC has, for the first time, given their experience of TKI
1 p0 u7 q9 H; g: f; Gdiscontinuation. The doctors at MDACC look at 26 patients who
9 H3 V U1 X5 O0 sdiscontinued therapy from 2003-2012 for various reasons. These reasons
3 Q- O" {; \/ w" U; z- @include long time in CMR, adverse side-effects, pregnancy and financial
7 X2 c* @. E# P/ I. Q9 {% c2 {constraints. Please note that 17 patients discontinued therapy in CMR
6 [* j# ?- q( G5 f; Aand the rest in MMR. Of the patients in CMR who discontinued therapy,7 d4 k; Z' I, e6 g+ P! i
47% had molecular relapse. Those in CMR who discontinued and had taken! v1 f! `7 G% l" C+ g/ T0 B
prior Interferon to a TKI, 50% relapsed. Also note that of these 26
" ~0 { m; e( a* Q/ j9 Q; I9 N$ |patients, most had been treated with high dose Gleevec.
! d' P, ` `7 a- t# ]- V+ H/ ~8 I# g' H, w% m. i( F5 o
"All patients discontinued therapy in CML-CP, all in CCyR, of them, 17
3 ~& e4 ?* c/ w5 q0 @- ]4 L% N(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR.
+ ]$ I5 L. H% B, F' F# P7 hThe median duration of CMR before TKI cessation was 62 mos, (0- 118).5 G( ^6 Z) ^$ O/ y8 `; o8 M6 ]
The median duration of total TKI therapy was 101 mos (3- 135)."7 r" p$ b5 t) K7 f
& r6 J8 f& _3 m& lTherefore, the median time in CMR before discontinuation was about 5* P0 I$ A) F I+ R
years. The median follow-up is only 11 months. The median time for
( ?* P% ^* P& K2 L' x" kmolecular relapse of 8 patients who had been in CMR was 4 months and+ \+ y0 h) J& t, r) x
they relapsed with median PCR value of 0.01 on the International Scale.
( F2 F+ X5 o7 I* Q' d5 C3 {* ]
$ o& [( g1 w8 ]2 `3 ?6 t2 i4 \Of the 7 patients who discontinued when in MMR, 4 remained in MMR at a/ }2 O& K) E; J' M" P
median follow-up of 21 months, 1 remained in CCR, 1 in active disease
+ H. K ~6 i6 O, L( l$ B7 ~& ]and 1 transformed to accelerated phase off drugs. Therefore, from this
, N6 _) Q" B+ a$ P" y9 ^2 W" bdata, scarce as it is, there is a risk of transformation to advanced' `- K/ d/ _/ \( b4 p/ `
disease if one discontinues drugs in MMR.
. Y3 u o3 p1 L' f2 q' | A& i
2 patients were PCRU (4.5 log machine) and these patients relapsed
. I8 U: T: a2 l0 j8 Rinto MMR when drugs were discontinued. c+ [0 o! o" @$ r) U+ I
$ Z; r! R: `9 x6 [' W, |0 `$ T
Seven pts with relapse were treated again with TKI, 3 with nilotinib,
) \- y! w c, u& _# ^3 ^2 with dasatinib, and one each with imatinib and bosutinib (the latter: U* _9 C' K2 N) b( `8 x
in AP). After a median of 13 months on therapy (range 4-52) all patients
- {7 r- {1 Z" d* m; d: [1 z7 limproved their response, 5 with CMR and 2 MMR (including the pt that had# b6 u( |7 h3 `" \/ z
transformed to AP). They do not say why all patients were not retreated
4 i$ G' L! k, h% dwith imatinib and had to take Nilotinib and Dasatinib. Also, note that
5 P3 u; L) y8 `: S3 \: Y: jone did not regain CMR at the 13th month mark though it is good news4 Y# \) a; g" h& M* v1 z4 l
that 5 did. It may take some time to regain CMR for some who have gone& n1 P+ K4 L; v- P- O3 F( z
off drugs and relapsed. However, from our own list experiences, some
O0 \8 [! q# M4 J' q% g" z: p2 zhad regained CMR fast when they retook the TKI.7 Y2 ~5 u8 A7 \7 s
& l+ F+ P" t: x) L/ \
The doctors conclude that treatment discontinuation is experimental T/ a2 Q$ Z/ M. y) W! N$ e3 G
and cannot be recommended at this stage as a standard procedure.4 k+ L0 G; G& q2 R) G/ X/ p
5 D: z- O( A5 y7 }& e& {Best Wishes,
! k" Y. c% N( ~+ r6 A- y* N( i% M% m- u6 B5 l
Anjana( G8 I3 [# K& U- c
+ n9 o! M! n1 ~
, x- q- f( w2 I8 a/ J6 o8 b0 c7 l. ]& _
1 J# X. w @! G# c' d z( j/ j! G$ ^' r& ]6 r1 w
" k( J% ~& b" f# O
1 V( c8 Q7 s( n- g8 u$ f4 \4 V
u* U2 I" h+ v# U* t8 E) ^1 N# \. e% ^2 c7 H( @- ]7 V, ?
7 V3 L6 i2 l3 O4 F6 i3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor
' K' ~) r8 {5 ZTheray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single
8 X' _% @# z! \% dInstitution Experience
8 d Z, U* S! EProgram: Oral and Poster Abstracts
" y- O0 {2 @& V- LSession: 632. Chronic Myeloid Leukemia - Therapy: Poster III1 t8 t& T# _9 X/ n9 f7 a4 S
5 r# g: { y5 B. J `1 b
Monday, December 10, 2012, 6:00 PM-8:00 PM
% _5 S6 z$ R, U, `7 B7 `% ?! Z( i6 Z/ ?! ^, Z8 z$ _
Hall B1-B2, Level 1, Building B (Georgia World Congress Center)3 t' y# S+ M' r* P
2 q1 m4 `- H+ f
Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,5 D6 E& H% `6 d9 j" D7 J
Elias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,- }7 A2 u4 Z0 l7 {
Stefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,
7 Q3 S% I* s: {0 |9 F0 {" SGautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.
' F" H8 i$ X$ w& {8 {; E7 _0 x7 \Cortes, MD11 ~+ g7 D2 [! j. [5 b- ~8 D
: H5 x& O! z# K7 i8 q2 z1Department of Leukemia, The University of Texas MD Anderson Cancer
! {' O6 t- y1 J- @& rCenter, Houston, TX9 a- G0 H) Z% n5 S0 j
2Department of Leukemia, The University of Texas M.D. Anderson Cancer$ [* U, C' n# i& M
Center, Houston, TX
d" Z* b% A- l, v' k5 o' q9 N% l6 U* S' u% U/ |
Introduction: Some recent studies have reported on the outcome of CML: v$ B2 X6 q. O" r# D' V" L; |1 r
pts who discontinued thyrosin kinase inhibitors (TKI) after achieving
. O+ b0 l( H5 m3 }( v) osustained undetectable bcr-abl transcript level. Most patients who stop
H" R6 n# U4 J7 c# l9 X% }TKI have experienced molecular relapse. Most patients respond after [ |6 R x8 V9 U
resuming TKIs regaining undetectable bcr-abl transcript levels. These! n0 ^8 I$ A& D; _8 |) Y( A
series have prospectively planned treatment discontinuation and included
5 p5 i/ X# D1 A7 Ronly pts that have sustained complete molecular response (CMR) for at
i p: \- ~% E/ U; Nleast 2 yrs. However, in many instances pts may want to discontinue TKIs0 O: g6 }! [, j7 [( N* h7 h
not in CMR. Various reasons may lead patients to discontinue TKI
' h& s* }2 y: T7 R/ itreatment unexpectedly, among them severe adverse effects, pregnancy or# s8 H5 H, S+ t1 v6 Y* N
economic constraints. This single institution experience reflects the
% I8 f/ L3 g) j, Sheterogeneous nature of pt-driven TKI discontinuation.
; U; E; G6 j) D% N; c5 [* e3 K, Q2 B# \# o2 ]2 R3 p2 X& i1 k8 D
Aim: To characterize the outcome and profile of CML pts who chose to( Z+ U4 c$ `: G; M6 C6 k6 a# A& t9 s
discontinue TKI therapy in a single center regardless of their initial
- ~' T% l7 M: b' C. uresponse to TKI therapy.
5 a! e. m @$ V& A% J, y9 ?6 S# Q" K5 T6 A' u% J8 E* `
Methods:We retrospectively analyzed MDACC data on all patients with CML( b8 J% _ D" {' s( \' x, a
that were treated with TKIs in our institution and discontinued therapy.
1 G0 m7 p/ F4 N. ?+ ^/ g7 l& V; e' B9 B
Results: A total of 26 patients with CML-CP managed at MDACC
! v. Y' Q0 `4 U: Q% {; f5 zdiscontinued TKI between 2003 and 2012. The total median follow up time+ p& ] v& h3 \9 W2 p
since diagnosis was more than 120 months (mos) (range, 45 mos to 304
) ^' D* P0 j0 J3 i9 m# [/ u! O6 e4 pmos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were& p, [/ D7 B! s; [# |/ X2 U
female. All pts had been diagnosed and treated in chronic phase.' J! j) z- s6 c ]8 @2 o/ d
Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI0 ~( B4 |9 E" n7 v9 C- B9 v
as initial therapy (4 received imatinib 400mg/day, 10 imatinib* W! |4 m# \* l, r U) E( z8 r
600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with
: P( ~* g9 p7 `! }IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN
+ {2 Z" h* @* f: E1 v1 d0 y$ ?; zfailure. Pts treated frontline with TKI started therapy within a median$ R1 R( g* j' b- `! p6 \
of 0.8 mos from diagnosis (range 0 to 4) and those with previous4 M1 d9 b# v) V! y
interferon (n=11) after a median of 60 mos from diagnosis (31 to 164
4 T1 f6 o5 A( _8 B# }mos). Before TKI discontinuation 21pts (81%) were receiving their first3 Q/ g' y! o7 B. K
TKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete( f- m* W$ _+ p/ D9 {4 W1 q0 X0 D
cytogenetic response (CCyR) had been achieved in all 26 pts at a median
/ Z) u5 l' ^$ Y* e3 g# n5 }9 `1 ]of 3.5 mos (3-93); Major molecular response (MMR) in all at a median of9 C) L/ U* w; {6 k( A( k& W7 Q! U" C
9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All
' {3 H/ Q6 d8 ]+ d; T' Cpatients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)5 C8 w' B& _( w9 o
had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The \ \" U" T* {& O0 D: O5 \) }
median duration of CMR before TKI cessation was 62 mos, (0- 118). The
2 ?' O# m8 S5 h: {median duration of total TKI therapy was 101 mos (3- 135).: x5 o: R {8 R0 G3 u/ {8 `" L0 ~
2 J% r* J& A2 h
Fourteen pts (54%) discontinued TKI due to adverse events, 2 pts1 ~! M. R3 N$ W6 J
discontinued to become pregnant, 5 decided to stop after long CMR, and 5
# \8 V P9 i, r* y. y9 h3 }% Ppts discontinued for financial reasons. After TKI discontinuation
8 ?$ \3 V$ J/ }# xpatients were followed for a median of 11 mos (5-131). Among pts with
^7 Y, H7 q% X4 U* s+ ?8 h9 QCMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a
/ I1 N# F' M0 \% ^# a: {/ e( o3 Amedian of 4 mos (1-11) from discontinuation with median transcript level
) C; A2 c! Q) oat relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF5 m7 ?/ Q" I5 N2 z$ h& \
therapy had CMR at time of TKI discontinuation, 50% of them relapsed.5 h5 H. ^+ J. S
Among 7 pts who discontinued therapy in MMR, after a median follow-up9 ~& n6 w) Z9 H# u; \
from discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,) v+ n" p8 t% Y5 t* u! x7 i( h
one has minor CyR and one CCyR without retreatment at last follow up) \, S8 @3 z4 ]5 v" g- J8 w* I/ d
after 78 and 105 months from TKI discontinuation, and one transformed to
7 Q0 f3 {9 U: F0 N' Iaccelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed7 N2 b C* u* E; C F
to MMR. Three pts had a transient molecular recurrence with spontaneous6 }8 R }/ q! i- k& m
re-gain of CMR. Seven pts with relapse were treated again with TKI, 3; T$ `7 @1 E4 n5 @1 |0 i3 A
with nilotinib, 2 with dasatinib, and one each with imatinib and! C: G8 Y( y$ \9 J
bosutinib (the later in AP). After a median of 13 months on therapy
8 t* g8 l- P% k. C( O" @% I% ?(range 4-52) all patients improved their response, 5 with CMR and 2 MMR
- L F% w) V4 G(including the pt that had transformed to AP). There were no deaths or
. m9 U- `, ~! i y3 I2 n% Ntransformations to blastic phase of CML. At last follow up 14 (54%) pts* O) ~5 {- ~! s: b. W a+ e
were in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and
+ q1 u1 r6 G3 O; ?- KPCyR., {4 x" h& y! f( t8 i
1 @! h- X; v5 V3 SConclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular0 \; S$ r1 t2 H( B5 \) L
relapse in nearly half of the pts who discontinue therapy in CMR. Some5 k" g% @7 M0 d, d/ l; m: J: H( p2 t
pts who discontinue in MMR may have sustained MMR. Treatment
( K! B( r: E/ z: M# T6 ?. d0 l. wdiscontinuation should be considered experimental and cannot be
0 x8 ^; H: J1 A& }2 N4 crecommended to pts as a standard approach.2 H! |: C/ Z c& G
7 K3 r- ^8 T. {; W# C" g: C6 L2 |Disclosures: Ravandi: BMS: Honoraria, Research Funding. |