MDACC has, for the first time, given their experience of TKI7 p8 C, q; ?2 K* A. z
discontinuation. The doctors at MDACC look at 26 patients who
( L. E' \$ e* |& `, B& h k/ Xdiscontinued therapy from 2003-2012 for various reasons. These reasons. x. M1 U5 ^! Q T4 A% ~7 T3 Y: F
include long time in CMR, adverse side-effects, pregnancy and financial
/ ~$ G- w5 h: V A) z6 uconstraints. Please note that 17 patients discontinued therapy in CMR
+ e- ?$ P3 P8 W$ J+ p( ?and the rest in MMR. Of the patients in CMR who discontinued therapy,
6 g* u- ~) B* y2 t) P$ U. l) z! s/ v47% had molecular relapse. Those in CMR who discontinued and had taken9 L& G0 m L5 n& D6 p3 K; [
prior Interferon to a TKI, 50% relapsed. Also note that of these 26
$ U1 A! P" y+ ^7 U# O/ Apatients, most had been treated with high dose Gleevec.
+ n+ f {% T0 n& ?8 A) x. c
) ~, k0 S y" l"All patients discontinued therapy in CML-CP, all in CCyR, of them, 17+ b/ g/ j2 q$ f# U
(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. ?( P9 K( K7 P/ V
The median duration of CMR before TKI cessation was 62 mos, (0- 118).; H0 ?0 `5 o1 R! D- E: l2 d
The median duration of total TKI therapy was 101 mos (3- 135)."
" [. P- O" g6 h5 D) P$ D
0 d( L( s# u5 P0 |# rTherefore, the median time in CMR before discontinuation was about 5
$ H# Q$ e+ F" i8 f. Tyears. The median follow-up is only 11 months. The median time for
; h! K. v& P2 q9 D6 u) X* v; Nmolecular relapse of 8 patients who had been in CMR was 4 months and. g+ x3 N- l( O0 H! U
they relapsed with median PCR value of 0.01 on the International Scale.9 o, S# }( f- k' \
3 F# e; W* ?6 l- G8 O7 t7 h
Of the 7 patients who discontinued when in MMR, 4 remained in MMR at a
2 A. e. T8 ~ umedian follow-up of 21 months, 1 remained in CCR, 1 in active disease K% ]* l4 j9 O: r, i6 ^
and 1 transformed to accelerated phase off drugs. Therefore, from this
+ O! ` R6 A+ \% {, V: M' Ddata, scarce as it is, there is a risk of transformation to advanced
" C: n7 l3 t" q7 F* ~! n% Ndisease if one discontinues drugs in MMR.
* u3 ?9 H& k" `* c6 C! |/ B" w1 y. L+ m. { z8 M# `) p
2 patients were PCRU (4.5 log machine) and these patients relapsed
+ {3 o- b8 o+ F2 v- o2 r" D7 xinto MMR when drugs were discontinued.
a. _: ?# u- G+ N7 K' y
6 [0 Y' m! ]( g! {% B& iSeven pts with relapse were treated again with TKI, 3 with nilotinib,$ ~/ C, i( B4 U5 p6 z; Y% d4 F7 w' v, O
2 with dasatinib, and one each with imatinib and bosutinib (the latter
/ f$ R9 _4 c, c; b3 |8 e d! Lin AP). After a median of 13 months on therapy (range 4-52) all patients
4 `: X& N& o9 `# m1 kimproved their response, 5 with CMR and 2 MMR (including the pt that had
9 L! o# C Z) K9 |, {; h) A+ |transformed to AP). They do not say why all patients were not retreated
8 V9 ]4 g: P! F, X$ S( v/ bwith imatinib and had to take Nilotinib and Dasatinib. Also, note that- ] q W7 P0 M& A0 z7 y3 m
one did not regain CMR at the 13th month mark though it is good news9 U: `9 o% k9 _% P& l/ O
that 5 did. It may take some time to regain CMR for some who have gone
; I3 r3 ?; j& Y2 koff drugs and relapsed. However, from our own list experiences, some7 D! m- x1 w" e, y/ d
had regained CMR fast when they retook the TKI. R, K* M, w$ |* c; c0 |
L2 r2 X" s5 c# [5 c# O) s
The doctors conclude that treatment discontinuation is experimental
, p! T3 e* T- q d$ y" Eand cannot be recommended at this stage as a standard procedure.
2 j4 j. Q; c9 G6 `3 u2 W5 S6 E' E- f% j5 U! _' [
Best Wishes,
: V$ C7 T, Q3 R9 f1 q7 x9 }5 z
7 J+ Q6 w4 V2 lAnjana4 \7 u1 h7 w" P% c& N
4 i( L4 @' Z* |# x1 W/ j4 U# w# [, A& m) I0 v' w) h
% K |- O" @/ {$ Y' k" \, P8 r( w+ B E: H6 |
2 F# R2 V2 K8 `- I/ T$ ]6 I5 K
. Q- b7 {- y3 n8 M# u8 _2 c7 u0 w: ^: D5 Z* u/ Q
5 n* f/ _- o: _
. z, X* N5 H. M3 N: K0 F* R& u) \. P- E6 k4 I
3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor
, z; ]6 c8 O6 s2 D9 iTheray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single$ p/ O8 t1 D: ~% w
Institution Experience' I" X) z3 v7 }2 m5 `. s" A' q! m# G
Program: Oral and Poster Abstracts- K- V' B: r6 x2 S( w( L3 e
Session: 632. Chronic Myeloid Leukemia - Therapy: Poster III
9 U! U% b8 n. F$ q, r; r
. g0 b) h+ r( s4 hMonday, December 10, 2012, 6:00 PM-8:00 PM, b, }# @. V8 ~( Z+ w, D$ H* B7 P$ d
% w: c/ \ Q, I6 ~$ y! X& FHall B1-B2, Level 1, Building B (Georgia World Congress Center); c0 W$ x% X, {! O( L; F; k
6 Y. b3 P# b! e1 E
Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,
8 o) E7 W$ V, L$ x7 G& I hElias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,
" g* f1 f$ f7 Z0 X- KStefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,8 ]2 S. ~5 v1 I! x0 Z8 r/ H
Gautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.- U; _- C6 w3 ?3 ^3 o
Cortes, MD1
5 L% Z Q6 {- O0 N
9 I" d4 U( F7 s5 V1Department of Leukemia, The University of Texas MD Anderson Cancer5 i6 x0 [; u% j$ t! Z/ Y) x' Q! N
Center, Houston, TX0 M, Q! Q* d# h Y
2Department of Leukemia, The University of Texas M.D. Anderson Cancer4 J4 V) O" t. W$ ]. ~* h
Center, Houston, TX1 g9 R( H. L% e
( m' G, f% ^6 ]1 B
Introduction: Some recent studies have reported on the outcome of CML
& e2 ?' T7 ?: `9 upts who discontinued thyrosin kinase inhibitors (TKI) after achieving. H* X" x! C. k2 Q+ \$ T- Y
sustained undetectable bcr-abl transcript level. Most patients who stop1 ]9 ~6 [1 v' e4 w
TKI have experienced molecular relapse. Most patients respond after6 I& h6 X' G7 A1 s( w3 r" j$ Q
resuming TKIs regaining undetectable bcr-abl transcript levels. These/ ^- _+ c3 O) Q. `) F- I, d9 R" V
series have prospectively planned treatment discontinuation and included& h, c/ ^; V" J- g9 e$ R' |
only pts that have sustained complete molecular response (CMR) for at" u8 e& R% |5 Y3 f
least 2 yrs. However, in many instances pts may want to discontinue TKIs' Z1 _& o. j! x; }' f2 K/ R. D) N
not in CMR. Various reasons may lead patients to discontinue TKI
/ {( ]- B i! n3 S' N9 b4 H9 ]treatment unexpectedly, among them severe adverse effects, pregnancy or
8 z1 ~/ \- H+ p8 h) v; deconomic constraints. This single institution experience reflects the8 r+ G* x* g8 x6 k% s! v8 j: U
heterogeneous nature of pt-driven TKI discontinuation.) n6 g" _$ i! \: ]. }, Q
7 ]7 U+ o% X( v
Aim: To characterize the outcome and profile of CML pts who chose to
' B6 z: ], Q( Z+ m! [- e, |discontinue TKI therapy in a single center regardless of their initial: W2 F" e H$ i7 P' U( J& p
response to TKI therapy.
( v% K* n7 d+ O5 v7 s. `! n( q" C
# D3 ^; f, w" U/ V! K# VMethods:We retrospectively analyzed MDACC data on all patients with CML3 w. x" f7 ?. ~0 j9 n8 a) ]4 T8 W
that were treated with TKIs in our institution and discontinued therapy.$ Y/ _0 C! D2 \9 H" G
( s# D( R- i% x$ d9 GResults: A total of 26 patients with CML-CP managed at MDACC
5 U# k. ]& k$ m/ x/ [2 idiscontinued TKI between 2003 and 2012. The total median follow up time
5 {5 j- V% Y" r; u( f3 M, ?since diagnosis was more than 120 months (mos) (range, 45 mos to 3046 Y- P# k& {0 g- u, H( V* z
mos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were/ N5 l% n7 f% q
female. All pts had been diagnosed and treated in chronic phase." E: ^7 X7 ^$ ^
Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI$ ?6 c3 Z' g/ b% Q; p4 ~
as initial therapy (4 received imatinib 400mg/day, 10 imatinib& g, ~, ]% G2 J: ~' B. N/ ^
600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with5 w2 G; s x2 X3 n: M) E( k
IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN
- H5 m4 d/ \' F6 `$ a9 j: gfailure. Pts treated frontline with TKI started therapy within a median( x W) L5 ?3 v+ ]6 \
of 0.8 mos from diagnosis (range 0 to 4) and those with previous
7 E6 u& Z1 I8 g# k: g+ Z* Dinterferon (n=11) after a median of 60 mos from diagnosis (31 to 164
$ _" Z: ~6 Y, j3 ^1 d4 N4 qmos). Before TKI discontinuation 21pts (81%) were receiving their first$ _! x/ |0 x2 C
TKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete+ V+ H' s3 D+ o
cytogenetic response (CCyR) had been achieved in all 26 pts at a median. L4 `6 m3 ?9 L* k
of 3.5 mos (3-93); Major molecular response (MMR) in all at a median of& T( a# ?' Z k' E# i# q! n
9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All( D* \; {. C p: q/ l; Z, {
patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)3 q) F$ ~ l) `3 Z. T0 ]1 z
had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The, f( z3 c/ @$ r& y
median duration of CMR before TKI cessation was 62 mos, (0- 118). The
* z" E4 f1 q6 _# C' H" zmedian duration of total TKI therapy was 101 mos (3- 135). B0 Y- Q0 A! o' n! v' T- _" x! k
/ k# c9 o: c# hFourteen pts (54%) discontinued TKI due to adverse events, 2 pts
. W+ R1 Y9 _- x3 Zdiscontinued to become pregnant, 5 decided to stop after long CMR, and 5( U: T: M6 i1 M/ {
pts discontinued for financial reasons. After TKI discontinuation, r7 E; n/ h0 W
patients were followed for a median of 11 mos (5-131). Among pts with9 d! @" G2 U7 ?: _& J
CMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a0 v0 O% ?3 v5 c$ ^
median of 4 mos (1-11) from discontinuation with median transcript level
6 V) q. w0 t: k, P9 m# Tat relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF5 b+ M6 m v8 r! n: |* _
therapy had CMR at time of TKI discontinuation, 50% of them relapsed./ t0 U2 E& y' s. g
Among 7 pts who discontinued therapy in MMR, after a median follow-up
, S6 {) @8 a) b0 r0 ]/ [8 F1 F- jfrom discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,
- I# x' z, B4 |( i0 kone has minor CyR and one CCyR without retreatment at last follow up+ Y8 h* u6 t i
after 78 and 105 months from TKI discontinuation, and one transformed to
| M, K- E' w% k% x) r& saccelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed
8 N" i7 B5 k! ?' qto MMR. Three pts had a transient molecular recurrence with spontaneous
5 [+ y. R8 G9 f8 a; ]8 h- y3 hre-gain of CMR. Seven pts with relapse were treated again with TKI, 3
6 M: Q% J/ X, R6 cwith nilotinib, 2 with dasatinib, and one each with imatinib and J) R' B4 \4 ^( Z2 ~
bosutinib (the later in AP). After a median of 13 months on therapy" t- ?. e; @1 M* G
(range 4-52) all patients improved their response, 5 with CMR and 2 MMR
4 |! Y" U/ {1 m. ]5 R8 l: ?- {(including the pt that had transformed to AP). There were no deaths or
9 M! K- G+ u1 r. S& etransformations to blastic phase of CML. At last follow up 14 (54%) pts" ^1 Z5 a+ }0 D9 q- }+ c
were in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and
% l9 j9 {( \) B! `- w- J6 ~' d; L, zPCyR.
* ~5 I+ o" E! ]) ~
( B; N* [; t, l i( L& LConclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular! E1 M( w0 @. ?' n/ n
relapse in nearly half of the pts who discontinue therapy in CMR. Some
x! j5 H2 Y% h. U4 O# L$ m3 U: Upts who discontinue in MMR may have sustained MMR. Treatment
' I }' R- }. h+ qdiscontinuation should be considered experimental and cannot be
4 Q [- ~( d3 i: D9 C& Irecommended to pts as a standard approach.
: h. I+ B6 P) E# Z1 Z: x" M' M0 e' }( t" y; w7 }' c9 T0 I
Disclosures: Ravandi: BMS: Honoraria, Research Funding. |