MDACC has, for the first time, given their experience of TKI
' f1 l$ s9 [8 a- e$ I* y O, L8 Cdiscontinuation. The doctors at MDACC look at 26 patients who' Y: @; C+ k! x- E
discontinued therapy from 2003-2012 for various reasons. These reasons
; _* |! w% z# z' einclude long time in CMR, adverse side-effects, pregnancy and financial$ F. L# }, G1 A
constraints. Please note that 17 patients discontinued therapy in CMR: V: C6 c. O: Q
and the rest in MMR. Of the patients in CMR who discontinued therapy,
% N- C G, L: m {: {# _$ P47% had molecular relapse. Those in CMR who discontinued and had taken5 V6 A. e7 j: j: F
prior Interferon to a TKI, 50% relapsed. Also note that of these 26
( d: `7 K6 \$ V. g, Ppatients, most had been treated with high dose Gleevec.
1 b( j$ @8 s. _( G& B. j( `
# B% {9 T7 v- g4 U- ]1 U8 v% c"All patients discontinued therapy in CML-CP, all in CCyR, of them, 17" U* c1 E& r5 L: u- e
(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR." A( s) c' A* Y3 l9 ]1 C, V
The median duration of CMR before TKI cessation was 62 mos, (0- 118).
7 |( }) u) @) G3 M4 {/ _* O/ e+ z0 o4 EThe median duration of total TKI therapy was 101 mos (3- 135)."
9 `4 v: c. v* H+ h( f# P3 _* d9 ]! N( j; t' b
Therefore, the median time in CMR before discontinuation was about 5
9 @) z8 |* G2 z5 l8 _years. The median follow-up is only 11 months. The median time for
% p7 |4 z, B! ^" O5 F) _4 ymolecular relapse of 8 patients who had been in CMR was 4 months and
I- Q& B# }7 i2 E4 ythey relapsed with median PCR value of 0.01 on the International Scale.
+ d' }. Y, M8 n
/ H, A1 |4 c- F* V0 X1 DOf the 7 patients who discontinued when in MMR, 4 remained in MMR at a
% S' y& p: T3 B5 [; Zmedian follow-up of 21 months, 1 remained in CCR, 1 in active disease! Y2 U! G! D, }( |
and 1 transformed to accelerated phase off drugs. Therefore, from this1 |/ }- A: j. y2 ~
data, scarce as it is, there is a risk of transformation to advanced
9 i$ _- r# D/ vdisease if one discontinues drugs in MMR.
. W. k5 C$ j% u# \ j0 \
: H3 h- s7 l: r" I! ?2 patients were PCRU (4.5 log machine) and these patients relapsed6 H% d Y: Q$ K e, f- b
into MMR when drugs were discontinued.3 M8 w5 B/ n V3 P0 f# R
5 a9 h5 f% g2 D& b
Seven pts with relapse were treated again with TKI, 3 with nilotinib, X& w, i3 ?. g, h; F: H
2 with dasatinib, and one each with imatinib and bosutinib (the latter6 _. \2 T0 r$ [" q
in AP). After a median of 13 months on therapy (range 4-52) all patients/ R) u1 b7 v- J- Z& }% P# c
improved their response, 5 with CMR and 2 MMR (including the pt that had
( A! _/ c. r. A: {transformed to AP). They do not say why all patients were not retreated
4 q% P, j# M$ s: Rwith imatinib and had to take Nilotinib and Dasatinib. Also, note that
( j" f( j+ X- O. G4 ione did not regain CMR at the 13th month mark though it is good news9 E( V% K$ A" P
that 5 did. It may take some time to regain CMR for some who have gone o& x. I! b; ^! m1 x
off drugs and relapsed. However, from our own list experiences, some
! p- `* A0 T5 thad regained CMR fast when they retook the TKI.) J E) z" z" Q% n d9 i, g% h
1 _* d7 [7 O5 SThe doctors conclude that treatment discontinuation is experimental
" u: y2 g* n3 Sand cannot be recommended at this stage as a standard procedure.( c9 J6 p, f8 J$ J1 G/ j
4 C* k7 Q$ A! ?+ p' r& G& O3 Z' t
Best Wishes,
: S7 S/ P& l; T; J9 L$ C1 G8 e# j2 h2 {5 s6 Q5 d0 s
Anjana
, s5 {" ?; z1 |) z% J, T2 V7 D% {
6 v/ [2 L" `, n' y+ U+ e" L7 A0 ]& a$ @) s( D9 D4 e4 E
+ g" D7 q( J1 g3 |1 z4 f) z
4 F8 C' q) E7 i" k/ E0 K( g' B$ j" t0 O) @* J8 Z
; i7 ~3 g% x! R' U% T
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) Y8 g$ x, R' {; h7 a% j4 M3 @ E( ]% I- K- C
5 m9 `! p9 p( y( C; u2 F& k$ i3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor
+ g$ B9 P1 e5 {5 R2 L5 sTheray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single
3 {" N! S( Y+ X& F: i. ^! q1 \. {: y( ^Institution Experience/ P7 e: g0 f- O
Program: Oral and Poster Abstracts& M7 d" o4 r- D- x' x5 ~
Session: 632. Chronic Myeloid Leukemia - Therapy: Poster III
3 t! e6 }# U9 p3 ]- M. F" ?$ u1 k4 |6 N2 J$ x0 |! l/ Y! ?5 ^
Monday, December 10, 2012, 6:00 PM-8:00 PM* ~4 w3 Z- I, q' n9 w
" [* r: w: \$ {Hall B1-B2, Level 1, Building B (Georgia World Congress Center)) u }- [& M3 p C" ?
% H: d! U4 C1 f6 {0 ~4 U
Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,
6 u: b, r! w5 a2 ?Elias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,
9 W5 S9 n, t! m! _Stefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,
( {9 T; W6 i' R8 ^Gautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.( c* E) W% [4 z' R) m4 c. T4 n
Cortes, MD1
8 C1 m" x \3 y! B' o* C% B
+ I; b* P$ z" O) n1Department of Leukemia, The University of Texas MD Anderson Cancer
( }: e1 h% ?$ v& Z: YCenter, Houston, TX
: Z+ S1 y& G+ v0 c. i( C2Department of Leukemia, The University of Texas M.D. Anderson Cancer
& o- I5 E( y* _, I; }Center, Houston, TX
" b/ [: c3 u _! T9 L: P
; X( N& o: Q! M6 pIntroduction: Some recent studies have reported on the outcome of CML0 o! v* n9 a2 ]7 ?, L) g+ o
pts who discontinued thyrosin kinase inhibitors (TKI) after achieving W9 J9 w% I- C% U
sustained undetectable bcr-abl transcript level. Most patients who stop I; X6 n& c6 S& b3 e0 H; `' u9 j
TKI have experienced molecular relapse. Most patients respond after8 X7 l. `8 x5 ]
resuming TKIs regaining undetectable bcr-abl transcript levels. These2 R* j0 j/ s- P3 l9 n
series have prospectively planned treatment discontinuation and included/ I9 p" e* H7 q D' w) ~
only pts that have sustained complete molecular response (CMR) for at4 P' U( [# s) B* Q0 a
least 2 yrs. However, in many instances pts may want to discontinue TKIs6 |5 m( l E. d% ^& ~+ F8 F: S
not in CMR. Various reasons may lead patients to discontinue TKI$ i8 S. B6 L" ~3 ~% D8 D
treatment unexpectedly, among them severe adverse effects, pregnancy or$ N9 t5 {; s6 e9 i7 J
economic constraints. This single institution experience reflects the9 W2 |! W% z& `2 R, v
heterogeneous nature of pt-driven TKI discontinuation.% i! i; d+ L; h% ]7 j& E8 a
6 a4 Q$ [1 K9 T/ z
Aim: To characterize the outcome and profile of CML pts who chose to
- T- v. ~/ {: L, I4 ~ p) jdiscontinue TKI therapy in a single center regardless of their initial5 I! `# `- a" Q. `; i$ Q4 @
response to TKI therapy. G3 P. ^3 Y9 `- h- L8 I/ j
: V% z7 q" o# |
Methods:We retrospectively analyzed MDACC data on all patients with CML
, T9 A3 `; n5 V% x! Qthat were treated with TKIs in our institution and discontinued therapy.* m- C* ^9 D, p7 E6 @
( O; x) k- v$ n! N% U
Results: A total of 26 patients with CML-CP managed at MDACC m6 O) C* z- A$ O2 W5 J
discontinued TKI between 2003 and 2012. The total median follow up time3 ? m$ D, {9 z7 P
since diagnosis was more than 120 months (mos) (range, 45 mos to 304
0 b7 M; e+ }( U4 \- Q8 i& A. @) dmos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were
& W h6 @/ g0 l2 T0 A+ K2 D& X; B/ Afemale. All pts had been diagnosed and treated in chronic phase.
$ _0 d- U& O* F; A9 X2 a3 S9 X' PInterferon was initial therapy in 11 pts (42%) and 15 pts received TKI( C' g7 P9 L6 f% l' u
as initial therapy (4 received imatinib 400mg/day, 10 imatinib
4 [3 D; l& k& E$ Y3 H600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with
; @7 Z* x( ?& _5 u7 OIFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN6 ^& a! p1 Q1 F8 i9 m
failure. Pts treated frontline with TKI started therapy within a median
4 w6 X* u' @' c) ?of 0.8 mos from diagnosis (range 0 to 4) and those with previous: I' u9 H& w/ m& U2 S
interferon (n=11) after a median of 60 mos from diagnosis (31 to 164
& E/ @, T# m, h' Q2 @- m1 y9 {mos). Before TKI discontinuation 21pts (81%) were receiving their first
) F' {& s1 W2 b/ Z6 Y8 QTKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete& A# `) F) L/ u# s2 `
cytogenetic response (CCyR) had been achieved in all 26 pts at a median. V: o! k: D1 D% y& w& {: L: _
of 3.5 mos (3-93); Major molecular response (MMR) in all at a median of
7 V4 _( a2 _0 t. |2 v% @9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All) Q$ S! j7 G$ b" ?
patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)
9 \. X7 F4 U/ L3 a' Q2 Jhad undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The3 a1 P9 v& D- X. Z, i3 F. x" X
median duration of CMR before TKI cessation was 62 mos, (0- 118). The
, X, H/ |% w4 N; m( Imedian duration of total TKI therapy was 101 mos (3- 135).0 `8 G1 t% S9 r* X7 n: }2 b
& x. a' d. q1 }/ F
Fourteen pts (54%) discontinued TKI due to adverse events, 2 pts0 Z$ C, ]! ^7 k- |9 u0 C
discontinued to become pregnant, 5 decided to stop after long CMR, and 5
6 W7 J! c6 t$ N- O" v* k, L/ L* Jpts discontinued for financial reasons. After TKI discontinuation$ y: I" T; S. @* I! Y3 C
patients were followed for a median of 11 mos (5-131). Among pts with! f5 i4 `( y" W* R* _: @) z
CMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a+ r) A# i2 ^/ r1 t# R0 p7 T
median of 4 mos (1-11) from discontinuation with median transcript level
6 w$ L* v1 g3 V1 Z9 sat relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF1 W \6 Z9 E' z
therapy had CMR at time of TKI discontinuation, 50% of them relapsed.$ m6 Z) W5 v) L: o+ E( Z4 T* N4 A
Among 7 pts who discontinued therapy in MMR, after a median follow-up
8 ~* n/ g: w' _5 {3 J! ]( Ufrom discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,2 W1 H: I4 G1 n3 Y1 f
one has minor CyR and one CCyR without retreatment at last follow up
d4 }* u/ @/ ]0 G0 jafter 78 and 105 months from TKI discontinuation, and one transformed to9 B0 n: s, v& j9 \; g/ i
accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed+ x; g$ x6 d% g* o0 I
to MMR. Three pts had a transient molecular recurrence with spontaneous. l' U$ G6 Z4 T) }" c7 C3 @
re-gain of CMR. Seven pts with relapse were treated again with TKI, 3+ H2 \3 G1 B/ u" S
with nilotinib, 2 with dasatinib, and one each with imatinib and7 S0 w9 b, v6 ?" |: @! r
bosutinib (the later in AP). After a median of 13 months on therapy
, k' M9 B& V5 | c# I(range 4-52) all patients improved their response, 5 with CMR and 2 MMR
8 Q1 @7 v$ _ t g(including the pt that had transformed to AP). There were no deaths or3 V* K" ~: o% G5 R! H' ]
transformations to blastic phase of CML. At last follow up 14 (54%) pts
3 e" ^; s# E4 R) qwere in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and" q* C0 w, ^ Q+ }( Z- p) `% x T
PCyR.
W0 [2 O" T, B+ m* t* G' e4 P; ]" a) h1 r( s3 b
Conclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular" [) e7 z. G* }# K" S1 G- I
relapse in nearly half of the pts who discontinue therapy in CMR. Some: v7 r: q2 P' o( {4 s3 f
pts who discontinue in MMR may have sustained MMR. Treatment
1 t3 J w. e, f4 g1 g, _3 hdiscontinuation should be considered experimental and cannot be
* J; l X) p) P# c4 q9 C6 hrecommended to pts as a standard approach./ \, z; h- ~4 _& N% {) B! v: E" Q
w# a' j! {' S. r
Disclosures: Ravandi: BMS: Honoraria, Research Funding. |