MDACC has, for the first time, given their experience of TKI
% {/ I: m$ }* n1 s: f- W1 udiscontinuation. The doctors at MDACC look at 26 patients who5 H6 O9 e* ]% \1 T% W% N7 b: K0 L( T
discontinued therapy from 2003-2012 for various reasons. These reasons
% |' U5 w% `* v6 P, h8 \include long time in CMR, adverse side-effects, pregnancy and financial
4 ^1 ? t# S% V4 f. F y/ |constraints. Please note that 17 patients discontinued therapy in CMR2 g" \/ Y1 O/ w; z7 `, e ?
and the rest in MMR. Of the patients in CMR who discontinued therapy,, F& X& z* `; W$ X3 Y- P
47% had molecular relapse. Those in CMR who discontinued and had taken
; S7 _( ^, ^" c. u, J; z" S6 z6 w% Wprior Interferon to a TKI, 50% relapsed. Also note that of these 26
- U, a9 Y- t9 K. \, M( G1 @patients, most had been treated with high dose Gleevec.
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8 r, t U$ ^( ^- M# E"All patients discontinued therapy in CML-CP, all in CCyR, of them, 17
! v3 [4 J7 `( B) y1 y8 B(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR.
4 Q: X- g. i1 n, o4 Q: O$ d) {The median duration of CMR before TKI cessation was 62 mos, (0- 118)." F% N1 m( y% O+ U
The median duration of total TKI therapy was 101 mos (3- 135)."
U9 V$ j) Q( k# E) Q8 Y1 n3 A. j
1 K, F: I/ @) U! @& Q9 ^3 U6 P) U# }Therefore, the median time in CMR before discontinuation was about 5
8 m/ |7 s- v; Z2 p1 W' C+ M% ~) e* _years. The median follow-up is only 11 months. The median time for( p3 T! K) l- \' v3 {
molecular relapse of 8 patients who had been in CMR was 4 months and2 t* p i# }6 c6 d" E2 U; L
they relapsed with median PCR value of 0.01 on the International Scale.
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* B, I0 c x0 k# h7 C' NOf the 7 patients who discontinued when in MMR, 4 remained in MMR at a B' C8 e. \/ ]* e8 v
median follow-up of 21 months, 1 remained in CCR, 1 in active disease
1 Y+ p8 ?/ K8 |1 r( R$ ~; A) y/ ^' Gand 1 transformed to accelerated phase off drugs. Therefore, from this
2 n+ W1 k3 ~, @" C2 `data, scarce as it is, there is a risk of transformation to advanced* A" Q+ ] l$ z. U3 [! R
disease if one discontinues drugs in MMR.
3 [& E- @* d1 P& ]: ?9 h: s4 D6 B1 @! D, f, k+ j: m* I; V! j) R
2 patients were PCRU (4.5 log machine) and these patients relapsed
) N* s- z( m( Z2 Y: [3 E/ minto MMR when drugs were discontinued.: a- ]* X6 A: t4 N1 Y& {
/ k1 I# i- B. }Seven pts with relapse were treated again with TKI, 3 with nilotinib,
`8 A- W' @% d) F( W% ~; t2 C2 with dasatinib, and one each with imatinib and bosutinib (the latter
" s% K$ Q5 f* nin AP). After a median of 13 months on therapy (range 4-52) all patients
# j- Q3 d+ W/ P4 [" R2 n, n# C& Zimproved their response, 5 with CMR and 2 MMR (including the pt that had
- e' [2 H0 f1 n1 E: D# P4 i' Ltransformed to AP). They do not say why all patients were not retreated- F. u) o/ c& m
with imatinib and had to take Nilotinib and Dasatinib. Also, note that1 M+ p% m6 C9 S) W2 T# t
one did not regain CMR at the 13th month mark though it is good news& S/ Z3 m1 K4 R% g( |" T
that 5 did. It may take some time to regain CMR for some who have gone1 ?$ e" O9 H, m* }2 l2 j' O* d
off drugs and relapsed. However, from our own list experiences, some
0 _/ \6 C9 ^( Z5 ehad regained CMR fast when they retook the TKI.
; a8 d3 W1 m) {) `
" l: c+ g& f: n8 W* C4 yThe doctors conclude that treatment discontinuation is experimental N H) M% ~8 Z- B5 f
and cannot be recommended at this stage as a standard procedure.
; l! D1 ~/ R/ J+ l# n; ?- V: |! K% i V: @- q I5 ?
Best Wishes,& ~& ?1 ~0 J9 N; C0 v1 e5 n3 \8 w
! N# q* d" `3 e, o3 M" Q+ z
Anjana
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/ U6 O; F5 ?4 [4 {) _$ ^3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor
6 f K; ~3 N, I2 ]5 J6 e$ g; LTheray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single
- |' M" Y% C' ~! [* j p8 hInstitution Experience
8 h4 K$ g, I" R$ i! yProgram: Oral and Poster Abstracts
6 z* {! W- D! u$ o3 B: fSession: 632. Chronic Myeloid Leukemia - Therapy: Poster III
7 U6 v& j: h& F- A, M( c. K4 k
; X' A) c" U+ i, ^( {' ?Monday, December 10, 2012, 6:00 PM-8:00 PM
. u* X K8 R! n ^$ P5 j/ O2 v, |/ q$ n" |. b+ A& N8 h
Hall B1-B2, Level 1, Building B (Georgia World Congress Center)6 J6 q6 ~7 t8 Z v; v, f& d
0 l0 u7 g! z5 R0 P1 ]: p7 ~; {Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,8 q/ v3 a" }8 @9 O. P
Elias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,) p& P* @( H3 b) U7 r) A; Q
Stefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,# S5 P: u5 C* I' X! K) D8 T
Gautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.! r* m' ] w4 V! v
Cortes, MD1* U- |1 k# Y5 I9 M2 {# O
7 U( H" M6 L8 J! Q( i+ u3 u& X! n1Department of Leukemia, The University of Texas MD Anderson Cancer" }- K/ A4 A0 j
Center, Houston, TX
7 ~4 m7 |! }, i5 n2Department of Leukemia, The University of Texas M.D. Anderson Cancer# C7 U- Q* O* [- V" \& c4 G- e4 G
Center, Houston, TX
' W3 t* f; l8 F. _
" ?5 C$ ]7 |1 g) I5 f$ R9 U( O( E) OIntroduction: Some recent studies have reported on the outcome of CML
+ B9 k& T8 Y3 B0 T }; B: upts who discontinued thyrosin kinase inhibitors (TKI) after achieving1 n5 R5 ?0 N) M9 U! z4 n
sustained undetectable bcr-abl transcript level. Most patients who stop
) y" a" t" k* L6 N! HTKI have experienced molecular relapse. Most patients respond after
$ I3 u$ w. `. o/ Bresuming TKIs regaining undetectable bcr-abl transcript levels. These) i1 K" A. y: E) { c
series have prospectively planned treatment discontinuation and included
: e0 [( U' C+ x# U5 _* p: eonly pts that have sustained complete molecular response (CMR) for at$ T9 W* n1 I2 m. W0 l" ~: F
least 2 yrs. However, in many instances pts may want to discontinue TKIs7 R7 t$ I4 W2 O! }2 S: W4 K
not in CMR. Various reasons may lead patients to discontinue TKI
- S: T2 c7 f) b" A* z' S/ Q+ B0 D5 |treatment unexpectedly, among them severe adverse effects, pregnancy or
( Z% y Q2 T O D meconomic constraints. This single institution experience reflects the
0 g% |; u1 M1 d4 ]+ M' M; S- M0 ]heterogeneous nature of pt-driven TKI discontinuation.' g' u4 f; T3 b! }; k
: }8 s+ J% I7 B& F X
Aim: To characterize the outcome and profile of CML pts who chose to! S7 ~0 Y- ~2 p
discontinue TKI therapy in a single center regardless of their initial
/ C2 d8 W: F( X+ g! yresponse to TKI therapy.7 _: R3 P- B7 a9 J, G" m; c! z
0 |3 K2 Q: P4 v) Q9 }
Methods:We retrospectively analyzed MDACC data on all patients with CML
% q3 b8 _% l7 ?( V' T& tthat were treated with TKIs in our institution and discontinued therapy.8 m/ {" ~6 J9 ^0 O$ x
6 j! w- @. k$ }, ^* nResults: A total of 26 patients with CML-CP managed at MDACC
1 |& [; e: _+ `& O- r* adiscontinued TKI between 2003 and 2012. The total median follow up time; N5 v- u# T( Z+ U+ @, n
since diagnosis was more than 120 months (mos) (range, 45 mos to 3046 o ]8 O9 t2 O! t/ s9 j
mos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were4 Q+ k% m3 b+ Z1 c
female. All pts had been diagnosed and treated in chronic phase.* H! }7 E$ G6 }( B$ e' u
Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI* E( t. ?9 ^: D+ T5 t( d
as initial therapy (4 received imatinib 400mg/day, 10 imatinib
! h9 _. V# P; O! y5 L2 t. ^& ?4 t600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with5 S* t. o. ^& D0 r& P2 v! i
IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN
0 L, T/ _. p7 rfailure. Pts treated frontline with TKI started therapy within a median
$ ?6 @1 n0 R5 b# Y1 E0 r4 O6 Fof 0.8 mos from diagnosis (range 0 to 4) and those with previous8 x2 |9 s, V( w: G, M' J% z) K
interferon (n=11) after a median of 60 mos from diagnosis (31 to 1640 x' H7 g7 x8 R- \, l7 V( T5 o
mos). Before TKI discontinuation 21pts (81%) were receiving their first
( k5 x* D9 d) J# y: o4 zTKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete7 c1 M6 L E, d+ K; D
cytogenetic response (CCyR) had been achieved in all 26 pts at a median9 V3 j) h6 j4 T+ K" @0 l
of 3.5 mos (3-93); Major molecular response (MMR) in all at a median of
- S# y2 d1 H$ y: c t9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All4 z3 I1 t/ Q2 W/ [$ ^2 n
patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)4 J. o9 R6 @ a2 b. i+ D2 K
had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The
9 |! `4 V$ l& C- [8 Zmedian duration of CMR before TKI cessation was 62 mos, (0- 118). The
3 l4 y' @4 l& R& u/ g Ymedian duration of total TKI therapy was 101 mos (3- 135)./ j0 r1 |2 V. A/ T, o! V
" | t& x7 n9 DFourteen pts (54%) discontinued TKI due to adverse events, 2 pts
0 G) [+ w5 p* a" K1 G$ h' l6 W) mdiscontinued to become pregnant, 5 decided to stop after long CMR, and 5
/ l2 E* y9 a, a8 r% R& b& z+ `7 }pts discontinued for financial reasons. After TKI discontinuation6 v3 }0 g& @/ a
patients were followed for a median of 11 mos (5-131). Among pts with
5 J0 r8 I) ^9 }! a' _6 A; _" jCMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a9 T5 Q f% T y+ c
median of 4 mos (1-11) from discontinuation with median transcript level
5 |) K2 R& k$ ]at relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF
9 H0 I6 \% i3 `. @7 L itherapy had CMR at time of TKI discontinuation, 50% of them relapsed.$ i# l" a, {- g+ |+ T8 ?" ~
Among 7 pts who discontinued therapy in MMR, after a median follow-up( l& s* }$ L! N4 z3 G6 T5 w. L
from discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,7 m j# a+ Q; |% Z. p
one has minor CyR and one CCyR without retreatment at last follow up/ c' r. e b r) b) s1 a$ U
after 78 and 105 months from TKI discontinuation, and one transformed to- ~, o" B! p: d* I
accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed) u3 J8 T* N% v
to MMR. Three pts had a transient molecular recurrence with spontaneous+ x# O" P! q$ {6 m' |4 ^% H
re-gain of CMR. Seven pts with relapse were treated again with TKI, 3# b& t+ M9 c# v, {/ G/ s5 A
with nilotinib, 2 with dasatinib, and one each with imatinib and7 `% b2 x/ L( `7 b8 R
bosutinib (the later in AP). After a median of 13 months on therapy
1 u( F& C; G/ J+ t: w0 i(range 4-52) all patients improved their response, 5 with CMR and 2 MMR
8 C; }4 h4 }5 t0 F0 ?(including the pt that had transformed to AP). There were no deaths or
+ W3 j2 l8 o) u2 F' Ntransformations to blastic phase of CML. At last follow up 14 (54%) pts
. |$ y) I: v/ m2 nwere in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and1 @1 ]; q) ^* d
PCyR.: X, z( \- D, h3 {
# ]( r' O" P2 J, [& J, G: XConclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular
$ w9 y6 r8 c2 g. s1 g/ lrelapse in nearly half of the pts who discontinue therapy in CMR. Some
) ]" }; A' J" l6 }pts who discontinue in MMR may have sustained MMR. Treatment
$ U" N1 `% t' Gdiscontinuation should be considered experimental and cannot be& ]( P2 @8 @* D( L6 K+ n
recommended to pts as a standard approach.5 ]8 Q0 t3 C, d# m& W) t2 i+ R* T
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Disclosures: Ravandi: BMS: Honoraria, Research Funding. |