1. No category

What is New in CML
in 2011
Hagop Kantarjian, M.D.
February 2011
1
CML. Historical vs. Modern Perspective
Parameter
• Course
• Prognosis
• 10-yr survival
• Frontline Rx
• Second line Rx
Historical
Fatal
Modern
Indolent
Poor
Excellent
10%
84 - 90%
Allo SCT;
IFN-α
Imatinib;
nilotinib;
dasatinib
New TKIs;
allo SCT
?
2
“Today, CML is an indolent disease.
Patients can be functionally cured and
live their normal expected life span,
provided they continue treatment with
oral TKIs (imatinib). CML is now a
condition like diabetes, hypertension,
CASHD, which, treated appropriately,
should result in a normal life”
Hagop Kantarjian; Somewhere, 2006
3
CML in US. Incidence vs. Prevalence
The Changing Demographics of CML
• Incidence 5,000 cases/yr
• Prevalence plateaus when
incidence = annual mortality
2% Annual Mortality
X Incidence of 5000 cases = 100
Prevalence of 5000 X 100 ÷ 2 =
250,000 cases
Kantarjian. CML Chapter. Abeloff’s Clinical
Oncology 4th Edition, 2279, 2008.
CML in US. Incidence vs Pervalence
Kantarjian. CML Chapter. Abeloff’s Clinical
Oncology 4th Edition, 2279, 2008.
7
BCR-ABL Expression Sufficient for
CML Induction
LTR
BCR/ABL
LTR
STEM CELL
(Daley et al., Science 1990)
CML
8
9
H Neves. Blood 93:1197, 1999
Do We Need Bone Marrow At Dx?
• Assess % of blasts and basos
(10-15% have CML transformation at
Dx)
• Confirm Ph by CG; detect clonal
evolution
• FISH can be falsely positive
• QPCR can be falsely positive or
negative
10
Monitoring CML Course
• Cytogenetics
• Fluorescent in situ hybridization
(FISH)
• Quantitative PCR (QPCR):real time,
competitive
• Abl mutations
11
Monitoring Procedures in CML
• CG: tedious; only 20 metaphases (SD
± 15%); painful BM
• FISH: faster; 200 cells; PB; but false +
up to 5-10%
• QPCR: best use in CGCR; predicts
for relapse; variability up to 0.5 log;
use 1 source (PB) and 1 reliable lab
12
Monitoring CML in Stable CGCR. My
(Simple) Approach
•  FISH and QPCR q 6 mos (ensure
concordance and stability of high quality
CGCR; both tests can be false positive or
false negative)
•  Marrow CG q 2-3 yrs; more often if
abnormalities in Ph-negative diploid cells
(eg chromosome 5 or 7 abn)
•  Mutation analysis only if imatinib failure or
change of Rx
•  Do not order imatinib plasma levels
How Do I Use FISH and QPCR Monitoring
in CGCR?
FISH
QPCR
Interpretation
Neg
<0.1%
Excellent response; FU 6 mos
Pos
<0.1%
Neg
>1%
FISH and QPCR false + or
false -; FU 3 mos
Neg
0.1-1%
FU 6 mos, FU 3 mos if one log↑
Pos
>1%
Check marrow + CG; ? relapse
Course of CML in CGCR on Imatinib
Highly Stable and Predictable
•  Historical fear of “sudden blastic
transformation”
•  On imatinib, sudden transformation may
still occur, but: rare, usually in first 2 yrs,
usually lymphoid BP in younger pts,
usually responsive to HCVAD + TKI
•  Closer monitoring in first 2 yrs
•  Monitoring in stable durable CGCR Q 6 mo
(I like FISH + QPCR – check for
concordance)
Analysis of Mutations in CML
•  If CG or hematologic relapse, mutations
studies help
•  No role for mutation studies pre-Rx or in
imatinib responding patients
•  T315I: no role for new TKIs; allo SCT or
others (HU, ara-C, HHT, “T315I inhibitors”)
•  Nilotinib IC50>150nM :use dasatinib (e.g. Ploop ,Y253H,E255V)
•  Dasatinib IC50>3nM :use nilotinib (e.g.F317L)
16
Kantarjian. Blood 111:1774-1780, 2007
CML Blastic Phase
Morphology
No
%CR
%OR
• Myeloid
247
13
25
129 (24%)
43
61
167
14
25
• Lymphoid
• Undiff/others
• Lymphoid BP
Px ± (<10%), Tdt + CD10, 19+
CD13, 33+ in 80% often Rx as
myeloid BP
17
Ph+ vs. PhLeukocytosis
Hypercellular BM
Splenomegaly
Ph +
(90%)
Ph-
BCR+
BCR-
Ph- MPD
Atypical CML
CMML 18
Therapy of CML in 2010
•  Frontline–Imatinib 400 mg/D → 800(?);
nilotinib 300-400 mg BID; dasatinib 100
mg/D
•  Imatinib failure - Nilotinib, dasatinib,
bosutinib
•  Allogeneic SCT
•  Investigational –T315I inhibitors, (AP24534,
DCC2036) omacetaxine, decitabine, TKIs
combos
19
•  Combining TKIs + old standards (HU, ara-C)
CML. Survival after Allogeneic BMT
1.0
1: Sib + CP1 (N=3,372)
2: Sib + Not CP1 (N=1,141)
PROBABILITY
0.8
3: Other Donor + CP1 (N=1,302)
4: Other Donor + Not CP1 (N=725)
5: All Patients (N=6,548)
0.6
0.4
0.2
0.0
0
4
8
12
YEARS
18
20
20
LTO03_5.ppt
CML. Survival after Allogeneic BMT
1.0
PROBABILITY
0.8
60%
15% mortality over 15 yrs
45%
0.6
0.4
0.2
0.0
0
4
8
12
YEARS
18
20
21
CML Survival after Allogeneic BMT
1.0
Imatinib
1: Sib + CP1 (N=3,372)
2: Sib + Not CP1 (N=1,141)
0.8
3: Other Donor + CP1 (N=1,302)
PROBABILITY
60%
4: Other Donor + Not CP1 (N=725)
5: All Patients (N=6,548)
0.6
45%
0.4
0.2
0.0
0
4
8
12
YEARS
18
20
22
22
Allo SCT. Second or Third Salvage?
•  Imatinib failure in AP, BP: new TKI as bridge to MRD,
then allo SCT ASAP
•  T315I mutation in any CML phase: AP 24534, other
T315I inhibitors, HHT, HU, others as bridge to MRD,
then allo SCT ASAP
•  Imatinib failure in CP:
–  if IC50 ↑, CE, or no major CG in 12 mos → allo
SCT (risk should be reasonable: young, good
match)
–  If not → TKI until failure
•  Age ≥ 70 yrs or if poor match: may decide to forgo
curative allo SCT option for several years of CML
control
Results with Imatinib in Early CP
CML – The IRIS Trial at 8-Years
•  304 (55%) patients on imatinib on study
•  Projected results at 8 years:
- CCyR 83%
- 82 (18%) lost CCyR, 15 (3%) progressed to
AP/BP
- Event-free survival 81%
- Transformation-free survival 92%
- If MMR at 12 mo: 100%
- Survival 85% (93% CML-related)
•  Annual rate of transformation: 1.5%,
2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%
Deininger. Blood. 2009;114: abst1126.
Population-Based CML Outcome in
Sweden
• 3173 patients diagnosed between 1973-2008
- Median age 62 yrs
80%
54%
37%
23%
21%
Bjorkholm, et al. Blood. 2010;116: Abstract 205.
Probability Event-Free
Event-Free Survival by
Treatment in ECP CML
Months
Cortes et al. Blood 2009; Abst# 338 & 341; Updated October 2010
Frontline CML Rx with IM 400, IM 400 +
IFN, IM 800
• 1022 pt with CML randomized to IM 400 mg/D
(n=324), IM 400 mg/D + IFN (n=350), IM 800 mg /
D (n=338)
% Cumulative Rate at 36 mo
MMR
CMR
IM 400
79
45
IM 400 + IFN
71
40
IM 800
82
57
• Conclusion – higher CMR rates with HD imatinib
Hehlmann. Blood 116: abst 357; 2010
Imatinib and Pegasys in Chronic Phase CML
• 636 pt randomized to IM 400 mg; IM 600 mg; IM 400 mg+araC; IM 400+Pegasys 90 mcg/wk
• Median pegasys dose 54 mcg/wk; 45% stopped pegasys in
yr 1
• % at 18 mos
IM+IFN
IM 400
IM 600 or
IM+ara-C
pvalue
MMR
62
42
50-53
.003
SMR (≤ 0.01%)
35
18
19-22
.001
24-moCMR
16
9
8
0.01
• 12-mo CGCR rates similar in 4 arms
• % 12-mo SMR (Q PCR≤ 0.01%) 30% with IM+ Pegasys vs.
14% with IM400 (p=0.001). % 24-mo rates 38% vs. 22%
(p=0.01)
• No difference in PFS or survival
Preudhomme. NEJM 363: 2511; 2010
IRIS. Survival Without AP/BC Worse If No
Major CG Response at 12 mos
Rx aim: major CG response (Ph ≤ 35%)
Response at 12 months
CCyR
PCyR
No MCyR
n= 350
n= 86
n= 73
Estimated rate at 60
months
97%
93%
81%
}
p<0.001
} p=0.20
29
IRIS. Survival Without AP/BC Worse If No
CGCR In Year 2 But Not Related To MMR
Rx aim: CGCR in Year 2+; no need for MMR
Response at 18 months
Estimated rate at 60 months
CCyR with >=3 log red. n= 139 100%
CCyR with <3 log red. n= 54 98%
No CCyR
n= 89 87%
p<0.001
p=0.11
CG Abnormalities in Ph-negative
Metaphases with IM Frontline Therapy
• 21/258 (9%) patients developed CG abnormalities in Phmetaphases after median 36 mo
• Most common abnormalities: -Y (n=9; 43%), +8 (n=9;
43%), -7 (n=5; 17%)
• 1 (5%; 0.4% overall) developed AML [-7]
Overall Survival
Progression-Free Survival
Warning?
Warning?
Jabbour. Blood 110:2991-5, 2007
Imatinib and Pregnancy
•  180 women, outcome available in 125 (69%)
•  Outcomes:
– 50% normal infants
– 28% elective termination (3 abnormalities)
– 12 infants (9%) with abnormalities
– 3/12 similar complex malformations
(exomphalos, kidneys, bones)
•  Conclusion: Women on imatinib should be
advised not to become pregnant
32
Pye. Blood 111:5505, 2008.
Imatinib Treatment Discontinuations
The French Experience
• 69 pts treated with imatinib for ≥3 yrs with CMR
(≥5-log ⇓) sustained for ≥2 yrs
– 34 prior IFN, 35 no prior IFN
• Median follow-up 21 mo (11-29 mo)
– 41 (59%) pts relapsed; all within 7 mo
• 53% prior IFN, 66% no prior IFN
• Probability of CMR 12 mo after stop: 47% post
IFN, 34% no prior IFN
• Peripheral NK cells significantly lower in
relapse pts at imatinib discontinuation
• All patients responded after imatinib re-start
Mahon . Blood 114: abst 859, 2009
STIM Study. Relapses
40 pts relapsed (loss of CMR) within the first
6 mos; one pt relapsed at M7.
STOP IMATINIB AND MOLECULAR RELAPSES
70
7
60
RELAPSE
Number of patients
15
CMR
50
13
40
69
30
1
62
3
1
1
29
28
47
20
34
33
30
28
28
27
10
26
23
19
18
17
13
11
9
M20
M22
M24
0
Selection M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
Follow-up
Mahon. Blood 114:abst 859, 2009
M11
M12
M14
M16
M18
CML. Criteria For Failure On Imatinib
•  No CG response at 6 mos (Ph 100%)
•  No major CG response at 12 mos
(Ph>35%)
•  No CGCR in Year 2+
•  CG relapse or hematologic relapse
•  Not failure criteria
- suboptimal CG response
- QPCR ↑ in CGCR
35
Baccarani. Blood 108:1809-20, 2006
Chemical Structures of Approved
BCR-ABL Tyrosine Kinase Inhibitors
CH 3
N
N
N
H
N
N
H 3C
N
N
H
N
N
N
CH 3
O
H
N
N C
H3
Imatinib
N
O
N
H
F
F F
Nilotinib
Imatinib
Dasatinib
36
Nilotinib vs Imatinib in Newly Dx CML.
Endpoints and Design
• Primary: MMR at 12 mos
• Secondary: CCyR by 12 mos
• Other: time/duration of MMR and CGCR, EFS, PFS, time to
AP/BP, OS
Newly Diagnosed
CML-CP:
• N = 846
• 217 centers;35
countries
R
A
N
D
O
M
I
Z
E
D
Nilotinib 300 BID (n=282)
Nilotinib 400 BID (n=281)
Imatinib 400 QD (n=283)
• Stratification by Sokal risk; MMR defined as ≤ 0.1% BCRABL(/ABL ratio) on International Scale
Saglio. NEJM 362: 2251, 2010.
37
Nilotinib vs. Imatinib in CML-CP.
MMR at 12 and 24 Mo (ITT)
P < . 0001
P < . 0001
P < .0001
% With MMR
P < .0001
n = 282
n = 281
n = 283
MMR at 12 months
Nilotinib 300 mg BID
n = 282
n = 281
n = 283
MMR at 24 months
Nilotinib 400 mg BID
Imatinib 400 mg QD
Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP.
CCyR Rates by 24 Mo (ITT)
P = . 0018
% With CCyR
P = .016
n = 282
n = 281
n = 283
Hughes. Blood 116: abst 207; 2010
% of Patients
Nilotinib vs. Imatinib in CML-CP.
Suboptimal Response and
Rx Failure by 18 Mo (ITT)
n = 282
n = 281
n = 283
n = 282
n = 281
n = 283
Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP.
Progression to AP/BC or Death on Study TKI
P = .0059
P = .0003
P = .0089
Number of Patients
P = .0196
0.7%
1.1%
4.2%
Without Clonal Evolution
Nilotinib 300 mg BID
0.7%
1.8%
6.0%
With Clonal Evolution
Nilotinib 400 mg BID
Imatinib 400 mg QD
Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP.
PFS on Study Rx (ITT)
Events
Estimated 24-mo
PFS
Stratified logrank test vs
imatinib
Nilo
300
n = 282
Nilo
400
n = 281
Ima
400
n = 283
5
4
12
98%
97.7%
95.2%
0.07
0.04
--
Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP.
Grade 3/4 Myelosuppression
% of Patients
21
12
4
4
11
10
12
9
5
Anemia
Nilotinib 300 mg BID
Neutropenia
Thrombocytopenia
Nilotinib 400 mg BID
Imatinib 400 mg QD
Hughes. Blood 116: abst 207; 2010
Nilotinib vs. Imatinib in CML-CP. DrugRelated Non-Lab AEs (≥ 10% in Any Group)
Nilo
300
n = 279
% Pts
Nilo
400
n = 277
<1
0
<1
All
Grades
21
7
7
Grade
3/4
1
<1
0
All
Grades
34
27
26
Grade
3/4
0
<1
1
5
0
9
1
18
0
Peripheral edema
Facial edema
Eyelid edema
Periorbital edema
Rash
Headache
Pruritus
Alopecia
5
<1
<1
<1
32
14
16
9
0
0
0
0
<1
1
<1
0
6
2
2
1
37
22
13
13
0
0
<1
0
3
1
<1
0
15
11
16
14
13
9
6
5
0
<1
<1
0
2
<1
0
0
Myalgia
10
<1
10
0
11
0
Fatigue
11
0
9
<1
10
<1
Nausea
Muscle spasms
Diarrhea
Vomiting
All
Grades
14
8
8
Grade 3/4
Ima
400
n = 280
Hughes. Blood 116: abst 207; 2010
Dasatinib Versus Imatinib Study In Treatmentnaïve CML: DASISION (CA180-056). Design
•  N=519
•  108 centers
•  26 countries
Dasatinib 100 mg QD (n=259)
Follow-up
Randomized*
5 years
Imatinib 400 mg QD (n=260)
*Stratified by Hasford risk score
●  Primary endpoint: Confirmed CCyR by 12 months
●  Secondary/other endpoints: Rates of CCyR and MMR;
times to confirmed CCyR, CCyR and MMR; time in
confirmed CCyR and CCyR; PFS; overall survival
Kantarjian. NEJM 362: 2260, 2010.
DASISION. Confirmed CCyR (ITT)
P=0.0086
Shah. Blood 116: abst 206, 2010
P=0.0366
DASISION. Confirmed CCyR (ITT)
• 
Likelihood of achieving CCyR at any time 1.5-fold higher with dasatinib
(stratified log-rank P<0.0001; HR=1.5)
Shah. Blood 116: abst 206, 2010
DASISION. MMR (ITT)
P=0.0002
P<0.0001
MMR, BCR-ABL ≤0.1%
• 
BCR-ABL
≤0.0032%
Likelihood of achieving a MMR 1.8-fold higher with dasatinib (stratified logrank P<0.0001; HR=1.8)
Shah. Blood 116: abst 206, 2010
DASISION. MMR BY Hasford Risk
Shah. Blood 116: abst 206, 2010
DASISION. Progression to AP-BP (ITT)
100
n/N
6/259
9/260
• 
• 
No patient who achieved MMR progressed to AP/BP CML
• 
Rates of progression-free survival at 18 mos 94.9% for dasatinib and 93.7%
for imatinib
5 patients who achieved a CCyR progressed to AP/BP CML (2 dasatinib, 3
imatinib)
Shah. Blood 116: abst 206, 2010
DASISION. Grade 3/4 Cytopenia
100
• 
• 
Grade 3/4 bleeding occurred in 2 pts on dasatinib and 3 pts on imatinib
6 pts on dasatinib and 3 pts on imatinib D/C Rx due to cytopenia
Shah. Blood 116: abst 206, 2010
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP.
Forest Plots Comparing Differences in AE Rates
Anemia, grade 3/4
Neutropenia, grade 3/4
Thrombocytopenia, grade 3/4
Myalgia*
Nausea
Vomiting
Rash
Diarrhea
Fatigue
Headache
Fluid retention
Superficial edema
Pleural effusion
–0.4
–0.2
0
0.2
0.4
Rate difference (dasatinib–imatinib) with exact 95% CI
*Myalgia = myalgia, muscle
inflammation and MSK pains
Favors dasatinib Favors imatinib
Kantarjian. NEJM 362: 2260, 2010.
Bosutinib vs. Imatinib in CML Frontline Rx.
Design
Phase 3 open-label trial in
newly diagnosed chronic
phase CML
N = 502
139 sites
31 countries
R
A
N
D
O
M
I
Z
E
Randomization is stratified based on Sokal risk
score and geographical regions.
●  Primary endpoint: CCyR at 12 mos
Bosutinib
500 mg/day
n = 250
5-year follow-up
Imatinib
400 mg/day
n = 252
5-year follow-up
1-year analysis
●  Secondary endpoints:
– MMR at 12 mos
– Duration of CCyR, MMR, and CHR
– Time to and rate of AP and BP
– Safety and tolerability
Gambacorti-Passerini. Blood 116: abst 208; 2010
Bosutinib vs. Imatinib in CML Frontline Rx.
Response at 12 Mos (ITT)
P = 0.601
P = 0.002
n = 250
n = 252
n = 250
n = 252
Gambacorti-Passerini. Blood 116: abst 208; 2010
P <0.001
P = 0.053
55
P = 0.065
Gambacorti-Passerini. Blood 116: abst 208; 2010
Probability of overall
survival (%)
100
95
90
Bosutinib
Imatinib
85
P = 0.117
80
0
0
12
24
36
48
Time to death (wks)
56
Gambacorti-Passerini. Blood 116: abst 208; 2010
Probability Event-Free
Event-Free Survival by
Treatment in ECP CML
Months
Cortes J, et al. Blood. 2009;114: Abstract 338 & 341. Updated October 2010.
Ponatinib (AP24534). Pan-BCR-ABL Inhibitor
• Rationally designed inhibitor of
BCR-ABL
• Active against T315I mutant
- Unique approach to
accommodating gatekeeper
residue
• Potent activity against an array
of BCR-ABL variants
• Also targets other
therapeutically relevant kinases:
- Inhibits FLT3, FGFR, VEGFR
and PDGFR, and c-KIT
• Once-daily oral activity in
murine models
Ponatinib
Avoids T315I
Ile315
Ponatinib
Imatinib
O’Hare T, et al. Cancer Cell. 2009;16:401-412
Phase 1 Ponatinib. Study Design
• Phase 1 dose escalation design
• Primary objective
- MTD or recommended oral dose
• Secondary objectives
- Safety and anti-tumor activity
- PK, PD and pharmacogenomics
• Ponatinib daily oral administration
- 2, 4, 8, 15, 30, 45 & 60 mg QD capsules
- 45 & 60 mg QD tablets
- Intra-patient dose escalation
• Expansion cohort at MTD
Cortes. Blood 116: abst 210; 2010
Phase 1 Ponatinib. Study Group (N=74)
•  Median age 56 yrs
Prior Rx
Ph+ Pts (n=60)
- Range 26-85 years
Percent
Imatinib
97
60 (44, 7, 9)
Dasatinib
90
Ph+ ALL
4
Nilotinib
57
AML
6
52
Other (MM, MDS,
4
Dasatinib &
Nilotinib
Omacetaxine
18
XL228
12
Bosutinib
10
MK-0457
5
INNO-406
3
Dx
CML (CP, AP, BP)
MF)
N=74
Prior TKI
Ph+ Pts (n=60)
Resistant ≥2 TKIs
95%
Resistant ≥3 TKIs
65%
Cortes. Blood 116: abst 210; 2010
Phase 1 Ponatinib. Best Response in
CP CML
Best
Response
CHR
MCyR
CCyR
Overall
N=38
36 (95)
25 (66)
20 (53)
N (%)
T315I
N=9
9 (100)
9 (100)
8 (89)
Non-T315I
N=29
27 (93)
16 (55)
12 (41)
Cortes. Blood 116: abst 210; 2010
• 
Phase 1 Study of Ponatinib.
Duration of CG response (CP)
25 pts with CML CP in MCyR; 23 pts still on Rx; 21 still in MCyR
3 pts lost response (1 at 4 mg; 2 at 15 mg)
1 pt D/C due to AE (30 mg)
Duration
1 Yr
Total n=25
78%
T315I n=9
89%
Other n=16
69%
Cortes. Blood 116: abst 210; 2010
Omacetaxine for CML CP After
Failure to ≥2 TKI
• 85 pts with CML with 2 (n = 48) or 3 (n = 37) TKI
• Omacetaxine 1.25 mg/m2 BID x14d, then x7d
• Median follow-up 14.1 mo (0.3-42+)
IM + Das IM + Das +
Overall
or Nil
Nil
Response, %
N = 61
N = 48
N = 37
CHR
79
65
73
MCyR
25
14
20
CCyR
13
8
11
• Median duration MCyR 7.4 mo (0.9-26+ mo)
• Median survival 30.1 mo
Cortes J, et al. Blood. 2009;114: Abstract 644.
CML in 2010
•  Imatinib,nilotinib,dasatinib are
standard
frontline Rx (except p190 CML)
•  Dose optimization and adequate
monitoring
•  Sub-optimal response
– ⇑ dose imatinib (400mg → 800mg)
– New TKI
•  Failure
– Dasatinib, nilotinib, bosutinib
– Allogeneic SCT
•  T315I: AP24534, DCC2036, omacetaxine
Leukemia Questions?
• Pager:
713-404-3387
• Email:
[email protected]
• Hagop Kantarjian, M.D.