MDACC has, for the first time, given their experience of TKI
& |4 [+ M/ F8 V6 jdiscontinuation. The doctors at MDACC look at 26 patients who
# j, G6 @; S3 l" U8 G2 wdiscontinued therapy from 2003-2012 for various reasons. These reasons' {3 P4 I+ ^8 g g" p, O
include long time in CMR, adverse side-effects, pregnancy and financial4 l0 P) L3 g: {$ I
constraints. Please note that 17 patients discontinued therapy in CMR
" }. ?2 Z2 ]$ n; sand the rest in MMR. Of the patients in CMR who discontinued therapy,
6 _) _/ S5 @5 ]3 u; \47% had molecular relapse. Those in CMR who discontinued and had taken
% p A/ n$ ~( u: b' b7 nprior Interferon to a TKI, 50% relapsed. Also note that of these 26% V$ d5 f4 o. V. q8 u+ c; q3 `7 D. P
patients, most had been treated with high dose Gleevec.
* i- Z, u, w/ h3 F7 [, M2 L+ F
- n1 }4 y* E- t) a"All patients discontinued therapy in CML-CP, all in CCyR, of them, 171 I/ X1 z4 x0 C7 n4 g0 u
(65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR.
# F; b3 H& _; k0 y& m# h' d$ Q8 }The median duration of CMR before TKI cessation was 62 mos, (0- 118).
0 p# X1 R( u6 L, @; h" QThe median duration of total TKI therapy was 101 mos (3- 135)."/ E# o8 Z# ~3 J2 p; m( Q( e
4 J$ w$ ~8 \5 y) B$ S6 S5 @ S- i7 ]
Therefore, the median time in CMR before discontinuation was about 56 V' [. m+ J! i5 |2 _- w2 \
years. The median follow-up is only 11 months. The median time for
. c5 r3 y. U: B: ]; o3 Dmolecular relapse of 8 patients who had been in CMR was 4 months and; Z6 F; L7 s! }7 f% j
they relapsed with median PCR value of 0.01 on the International Scale.
+ \ M# \3 M! J' T( ]( Q2 q) @6 n4 {8 N8 c2 E( I. {( q
Of the 7 patients who discontinued when in MMR, 4 remained in MMR at a( l* a7 Z. K- [6 a
median follow-up of 21 months, 1 remained in CCR, 1 in active disease
4 u0 {6 R" w; f1 j& {and 1 transformed to accelerated phase off drugs. Therefore, from this
, K+ ^ `5 z% @0 A# Ddata, scarce as it is, there is a risk of transformation to advanced
; k- {" A' {; `$ \& wdisease if one discontinues drugs in MMR.: W) N5 Z Z3 t2 d
+ y! n+ K8 S& v' J# T
2 patients were PCRU (4.5 log machine) and these patients relapsed# ^& y$ N% I- q9 s
into MMR when drugs were discontinued.
* r6 A. A- J" q" i+ Y/ I* g8 B# Y3 @" z" P& \" V2 k% L
Seven pts with relapse were treated again with TKI, 3 with nilotinib,
, K* C0 l/ P5 O4 t) b8 X* B2 with dasatinib, and one each with imatinib and bosutinib (the latter
% k0 P {: \: l! [# Lin AP). After a median of 13 months on therapy (range 4-52) all patients0 i0 N+ F9 \) p0 h) Y+ n j: T; y
improved their response, 5 with CMR and 2 MMR (including the pt that had
9 L4 B: l B- Z( Itransformed to AP). They do not say why all patients were not retreated- U n I# G7 F' s9 Q, a$ y
with imatinib and had to take Nilotinib and Dasatinib. Also, note that
( B: u( N* J* i& @1 _1 h2 v6 bone did not regain CMR at the 13th month mark though it is good news; C2 G7 D) ?- j9 m
that 5 did. It may take some time to regain CMR for some who have gone# x" V1 b" _) I( h+ E2 K/ M
off drugs and relapsed. However, from our own list experiences, some
6 _# ^1 p: X) i2 O j% l' Ihad regained CMR fast when they retook the TKI.0 A" Q' p' ^% m" T+ Z
8 R2 A* ~' @( T% s8 k
The doctors conclude that treatment discontinuation is experimental
, T( u6 Q7 K1 g5 Jand cannot be recommended at this stage as a standard procedure.
( a" }' t0 a3 I: `9 ` Y# I. l
1 B& R. J+ F2 H7 b( gBest Wishes,
) o5 }. [1 l) @( E! q6 {2 D# I# m( n0 Y9 W
Anjana- f* ]$ W7 f' k8 M% g4 ~8 a3 n2 Y: o
2 y) O; | R8 x' z
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0 }) S7 ?) E! B! D Q, S* y
( Y8 `) t1 v' _- k- E j& b+ @7 A1 h) k1 M
2 S2 J' X: I2 ?. y! F* G
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7 v' _9 M, v5 u# c! {& m5 |( ]$ @. S" N! z4 A( F5 V! W* l
3783 Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor$ d c7 `7 [: O
Theray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single
4 b! y3 Y; o; ^# c2 k4 }Institution Experience& Q$ `( [4 J- i$ `& d# N* x0 n h
Program: Oral and Poster Abstracts
- K# S) g+ g& J- k! z1 W. r3 bSession: 632. Chronic Myeloid Leukemia - Therapy: Poster III+ S; N2 v3 P! }+ ^
4 {' r( Y& |- o. a3 J6 r
Monday, December 10, 2012, 6:00 PM-8:00 PM, e* f) S. t2 o# ]) _6 ~
5 y5 `8 r0 m/ ~" W2 L; I, {2 ]
Hall B1-B2, Level 1, Building B (Georgia World Congress Center)
, C& {2 O/ z0 q: o9 G8 X) G+ q! P- r
Ohad Benjamini, MD1*, Hagop M. Kantarjian, MD1*, Mary Beth Rios, RN1,9 D: M" S- L( f" d* Q
Elias Jabbour, MD2*, Susan O'Brien, M.D.1, Preetesh Jain, MD, DM, PhD1*,
/ ?3 @/ F4 z( yStefan Faderl, MD1, Guillermo Garcia-Manero, MD1*, Farhad Ravandi, MD1,
: E# P+ i j, l3 k2 C; `, eGautam Borthakur, M.D.1, Alfonso Quint醩-Cardama, MD1* and Jorge E.
- }# N1 C0 o' y3 K2 j8 \8 \Cortes, MD1
; |3 e8 g) J- D" Y& F) s/ V1 G
9 E) ~( n5 K( x) u1 |1Department of Leukemia, The University of Texas MD Anderson Cancer
/ T) S! X K3 K ]# e# [3 n4 v. r; C( ?Center, Houston, TX
- n5 @, S# }0 j! `+ C4 c$ I3 @2Department of Leukemia, The University of Texas M.D. Anderson Cancer6 y) ]9 Z3 `2 y* U: x) ?* q; { n
Center, Houston, TX3 l& e( Z5 ~3 d& W$ h6 {
7 R1 I6 b2 g0 g0 R$ g
Introduction: Some recent studies have reported on the outcome of CML# B" u" N! r8 i/ w
pts who discontinued thyrosin kinase inhibitors (TKI) after achieving, }( E* S) L V
sustained undetectable bcr-abl transcript level. Most patients who stop
9 R+ [- J n1 ]9 tTKI have experienced molecular relapse. Most patients respond after
5 U9 U: d' U5 [9 zresuming TKIs regaining undetectable bcr-abl transcript levels. These5 ^, T2 I) W, g% H
series have prospectively planned treatment discontinuation and included* b6 u" A+ y4 s
only pts that have sustained complete molecular response (CMR) for at8 Q; ]! i0 K. p9 U
least 2 yrs. However, in many instances pts may want to discontinue TKIs
9 z6 v7 R% r7 K# l4 Snot in CMR. Various reasons may lead patients to discontinue TKI
' u( g$ I6 w8 o: atreatment unexpectedly, among them severe adverse effects, pregnancy or0 d- ^8 G. T; O+ m) _: w5 c
economic constraints. This single institution experience reflects the/ N b3 ?# G8 U8 B1 k/ j( W
heterogeneous nature of pt-driven TKI discontinuation.5 Y9 Z+ ^/ }6 q
1 ]( U, K1 _ j3 z1 C! |
Aim: To characterize the outcome and profile of CML pts who chose to
7 X+ g. N Z. s1 Ddiscontinue TKI therapy in a single center regardless of their initial
/ j! M* H. f( Fresponse to TKI therapy.
4 N$ V) Z2 o. Z( l$ L' _( q. u3 x6 q" C8 L5 q [
Methods:We retrospectively analyzed MDACC data on all patients with CML& ~! Q0 J1 s1 [4 U: A8 B
that were treated with TKIs in our institution and discontinued therapy.+ z% @) Y; p- ] Y0 J0 \
% I# m4 y6 J& K: B. }, V2 Q
Results: A total of 26 patients with CML-CP managed at MDACC% D+ E8 @( g) d5 _) K& _* U2 u0 }
discontinued TKI between 2003 and 2012. The total median follow up time
$ s2 }& k2 R7 [! q1 v, q& ?since diagnosis was more than 120 months (mos) (range, 45 mos to 304
9 B$ n- _2 S6 l8 c$ T% F1 \! Mmos). The median age at diagnosis was 48 yrs (range, 28-73); 15 pts were
9 r& ^5 K3 r$ n$ d" f2 Mfemale. All pts had been diagnosed and treated in chronic phase.6 U; j$ x% n. a' g. S8 H4 |
Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI
( z0 F4 F% S2 p V# W8 s1 W0 \as initial therapy (4 received imatinib 400mg/day, 10 imatinib# s+ D+ N" Z |/ n' J! v0 f: m- J
600-800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with
2 t+ T" m9 J( j3 P% |IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN$ v- R' \1 O- i( c. F, H
failure. Pts treated frontline with TKI started therapy within a median
* Z/ T) V- g) \% B/ x8 hof 0.8 mos from diagnosis (range 0 to 4) and those with previous9 r8 k$ m+ _% ~( N& O6 j5 f: m
interferon (n=11) after a median of 60 mos from diagnosis (31 to 164' {9 Y$ p b) E* r
mos). Before TKI discontinuation 21pts (81%) were receiving their first
7 ~& e, j6 e: g; V5 I3 Z! |TKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete2 Q& `1 n1 \& x r8 d( j3 K% `
cytogenetic response (CCyR) had been achieved in all 26 pts at a median1 E% Q' G! r0 m$ H; x/ j
of 3.5 mos (3-93); Major molecular response (MMR) in all at a median of
8 P9 R p, l/ i$ Z N6 a9 mos (3-73) and CMR in 17 (65%) at a median of 22 mos (9-120). All
3 X; H; K$ T n B3 z5 Y, Z, ^patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%)
6 D/ A3 g2 A2 {4 i% ?had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The
- M& g3 W( i _: k' Fmedian duration of CMR before TKI cessation was 62 mos, (0- 118). The! d% D. Y4 c" h: P( c
median duration of total TKI therapy was 101 mos (3- 135).
* C1 r7 w$ U* H2 d2 X
8 V) B' z0 L1 a+ ZFourteen pts (54%) discontinued TKI due to adverse events, 2 pts
) e' b* D6 i d; P6 Rdiscontinued to become pregnant, 5 decided to stop after long CMR, and 5
/ F9 j$ ?3 ^2 o1 k& c, {pts discontinued for financial reasons. After TKI discontinuation
5 x0 O' K0 W0 \1 Npatients were followed for a median of 11 mos (5-131). Among pts with% Y3 U. N& z" ?" C
CMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a
3 p. s4 r4 Q! S* |3 }0 Imedian of 4 mos (1-11) from discontinuation with median transcript level! ]- o& F+ w+ G c8 s
at relapse of 0.07 (IS) (range, 0.004-2.17). Six pts with initial INF
! Y3 B" U; ~4 q; c, I9 dtherapy had CMR at time of TKI discontinuation, 50% of them relapsed.
; W5 m7 p9 ~; s3 ^1 V9 x& sAmong 7 pts who discontinued therapy in MMR, after a median follow-up
0 n- Q" _4 e0 g8 q$ ?0 @from discontinuation of 21.6 months (range, 4.6-106), 4 remained at MMR,
4 R1 S) e. W K/ r: a, ]0 q$ sone has minor CyR and one CCyR without retreatment at last follow up& i5 W# y/ o! y- m3 p' V6 k6 J' D
after 78 and 105 months from TKI discontinuation, and one transformed to& E } ]+ I& v; ~
accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed. B9 {* \6 o9 ^' K, H' [8 C+ j/ f9 y: x
to MMR. Three pts had a transient molecular recurrence with spontaneous7 b5 `: I2 {/ @! R0 r& O" P4 }- |
re-gain of CMR. Seven pts with relapse were treated again with TKI, 3% s# O3 _2 K9 b+ B& d5 f
with nilotinib, 2 with dasatinib, and one each with imatinib and
% C3 c% N8 Z2 ^# T; zbosutinib (the later in AP). After a median of 13 months on therapy& e& e9 B6 I4 q1 N
(range 4-52) all patients improved their response, 5 with CMR and 2 MMR- P" g& u3 N+ l/ I5 P1 J8 m) X) j. A. Z
(including the pt that had transformed to AP). There were no deaths or
/ j+ c# t7 u, ^" q3 atransformations to blastic phase of CML. At last follow up 14 (54%) pts' @8 l! w1 k* T4 ?3 m
were in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and7 A4 H5 q3 e. s( ?
PCyR.
5 |( s2 _% x3 k" k% |9 t0 s2 w, y2 P* ^
Conclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular8 n3 @2 [+ B5 w: @! \! n/ w$ |% U
relapse in nearly half of the pts who discontinue therapy in CMR. Some) ~6 c0 I" B& I0 M6 z$ h" T: y* g
pts who discontinue in MMR may have sustained MMR. Treatment$ S8 D% U+ ]; ^3 y3 B
discontinuation should be considered experimental and cannot be) L# t! ~9 N5 Y
recommended to pts as a standard approach.
$ Z# ^) \; \. x% D$ v; ?/ G; D# D9 ^- [
Disclosures: Ravandi: BMS: Honoraria, Research Funding. |