Download CHRONIC MYELOGENOUS LEUKEMIA - 2012

CHRONIC MYELOGENOUS
LEUKEMIA - 2012
Charles A. Schiffer, M.D.
Karmanos Cancer Institute
Wayne State University School of
Medicine
Detroit, MI
DISCLOSURES
•  Consultant – Novartis, BMS, Pfizer,
Chemgenix
•  Grant support – Novartis, BMS,
Ambit
A minute chromosome in
human granulocytic
leukemia. Science 132,
1960, 1497.
P.C. Nowell, D.A. Hungerford,
University of Pennsylvania in
Philadelphia
…the findings suggest a
causal relationship
between the chromosome
abnormality observed and
chronic granulocytic
leukemia…
Chromosome 9
Chromosome 22
Philadelphia Chromosome
t(9;22) (q34;q11)
q11
c-BCR
BCR/ABL
reciprocal
translocation
q34
c-ABL
BCR/ABL (210 kDa)
c-ABL
c-BCR
1294
Y
177
Y
OD
Ser/Thr
kinase
DBL
SH3 SH2
Tyr
kinase
NLS
DNA
BD
actin
BD
CML CASE
•  A 32 year old woman had CML
diagnosed after she was found to have
a WBC of 130,000/mm3 with platelets of
722,000/ mm3 during a routine physical
examination
•  Peripheral blood cytogenetics showed
a t(9;22) without additional changes
•  She was begin on imatinib, 400 mg
daily
Nilotinib Versus Imatinib in
Patients With Newly Diagnosed
Philadelphia Chromosome-Positive
(Ph+) Chronic Myeloid Leukemia in
Chronic Phase (CML-CP):
ENESTnd 3-Year Follow-up
Giuseppe Saglio, Philipp D. le Coutre, Ricardo Pasquini, Saengsuree
Jootar, Hirohisa Nakamae, Ian W. Flinn, Andreas Hochhaus, Timothy P.
Hughes, Richard A. Larson, Albert Hoenekopp, Neil J. Gallagher,
Richard Yu, Rick E. Blakesley, Dong-Wook Kim, Hagop M. Kantarjian
on behalf of the ENESTnd Investigators
‹#›
6
Study Design
R
A
Nilotinib 300 mg BID (n = 282)
N
•  N = 846
•  217 centers
•  35 countries
D
O
M
I
Z
E
D
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
*Stratification by Sokal risk score
*
Follow-up 5 years
7
Cumulative Incidence of MMR
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
100
90
n
282
281
283
% With MMR
80
By 3 Years
73%, P < .0001
By 1 Year
70
55%, P < .0001
70%, P < .0001
60
Δ 17%-20%
50
53%
51%, P < .0001
40
Δ 24%-28%
30
27%
20
10
0
0
3
6
9
12
15
18
21
24
27
30
33
36
Months Since Randomization
Data cut-off: 27Jul2011.
Number of Patients, n
Progression to AP/BC: Including Events
After Discontinuation (ITT Analysis)*
P = .0496
HR = 0.5 [0.2, 1.0]
P = .0076
HR = 0.3 [0.1, 0.8]
19
9
6
3.2%
2.1%
6.7%
On Core Treatment and After Discontinuation
Nilotinib 300 mg BID
 
 
Nilotinib 400 mg BID
Imatinib 400 mg QD
Off treatment progression information was prospectively collected for all patients
every 3 months after discontinuation
In the IRIS study, cumulative progression rates in the first 3 years of therapy were
approximately 6% on imatinib1
* Progression to AP/BC or death following progression.
1. Hochhaus A, et al. Leukemia. 2009;23(6):1054-1061.
9
Data cut-off: 27Jul2011.
Overall Survival
Patients Receiving Initial Treatment
Total Number of Deaths
Estimated 3-year
overall survival (OS)
Still on Core
Treatment
Nilotinib
300 mg BID
n = 282
Nilotinib
400 mg BID
n = 281
Imatinib
400 mg QD
n = 283
13
8
17
95.1%
97.0%
94.0%
71%
74%
62%
•  Of 38 total deaths on study, 23 were following progression to AP/BC
Data cut-off: 27Jul2011.
2764 Safety and Efficacy of Frontline
Nilotinib (Nb) for Chronic Phase (CP)
Chronic Myeloid Leukemia (CML) in
Diabetic Patients (pts)
•  Can make control of diabetes more
difficult
•  Hyperglycemia is manageable with
conventional approaches/medications
SUMMARY OF THE DASISION and
ENEST STUDIES
I
CyCR
MMR
D*
80%
41
ON THERAPY
81
AP/BC
3.5
N**
I
85%
57
87%
62
77%
80
2.3
74
0.7
67
37
4.2
*DASISION – 18 months F/U; **ENESTnd 24 months, 300 mg ARM
Hmmm….
•  Higher response rates
•  “Deeper” responses
•  Less early progression?
•  Good tolerabilty
•  And, imatinib is wonderful, but not perfect ~ 60% of chronic phase patients remain in
CyCR on imatinib at 5 years
Why would anyone use imatinib?
TRIAL DESIGNS USING SECOND
GENERATION TKIS “UP FRONT”
IMATINIB
$“X”vsvs$$
$ vs $$
MORE “REAL WORLD” DESIGN
“X” vs IMATINIB “X”
IMATINIB vs “X” ??
MY PREFERRED ENDPOINT
The fraction of patients in a
minimum of CyCR at 2 years with a
normal PS and a minimum of
symptoms who are either
- still taking the assigned drug
- or have switched to an
alternative drug per protocol
ISSUES
•  Large numbers of patients are no
longer receiving their assigned drug
•  Data as presented are not strictly
intention to treat
- incomplete information about patients
who went “off study” for reasons other
than treatment failure or progression
- this makes the curves “look better”
(Fleming, T. Addressing Missing Data in Clinical
Trials. Ann Int Med 154:113, 2011)
•  Emerging data about long term side
effects from dasatinib and nilotinib
•  Inadequate effect in patients in more
advanced stages of chronic phase
DASATINIB ≠ NILOTINIB
•  Long term side effect profile
• 
• 
• 
- Pleuro/pericardial effusions, pulmonary
hypertension – dasatinib
- Hyperglycemia, peripheral arterial
occlusive disease, chronic effects on
pancreas or bone metabolism (??) - nilotinib
Activity vs. other kinases differ
T/NK lymphocytosis with dasatinib (good or
bad??)
Compliance?? (daily vs bid)
GOALS OF THERAPY FOR CML
CHRONIC PHASE
IMAT
RAPIDITY OF RESPONSE
SUSTAINED RESPONSE
SHORT TERM TOLERANCE
LONG TERM TOLERANCE
BENEFIT IN HIGH RISK PTS
PFS
OVERALL SURVIVAL
OVERALL COST
STOP THERAPY
D,N
XX
??
XX
??
X
X?
???
XXX
???
A CLINICIAN’S DILEMMA
When to adopt “promising” results presented
at ASH, ASCO or even after receiving the
blessing of the FDA when follow-up or other
data are incomplete
Remembering the high degree of patient
selection/exclusion inherent in most clinical
trials
Other people’s money!
What if it was your own money?
ALTERNATIVE APPROACHES
•  Imatinib initially with switching to second
generation if inadequate response with
early endpoints
- lower risk patients
•  Second line initially with switch to imatinib
after MMR
AH….BUT WHICH DRUG?
HOW TO CHOOSE BETWEEN
(AMONGST) THEM?
•  Marketing
•  Comparative trials
•  Side effect profile
•  Evidence that effects other than bcr/abl
inhibition are important
•  Convenience – once vs. twice daily
without food
•  REMS for nilotinib
•  Cost
Progression to AP/BC* on Core Treatment
P = .0003
Number of Patients, n
P = .0085
P = .0059
17
P = .0185
12
2
0.7%
5
3
1.1%
Nilotinib 300 mg BID
2
4.2%
0.7%
1.8%
6.0%
Including Clonal Evolution
Nilotinib 400 mg BID
Imatinib 400 mg QD
•  No new progressions occurred on core treatment
since the 2-year analysis
* Progression to AP/BC or death following progression.
23
Data cut-off: 27Jul2011.
• 
Six months later, a peripheral blood
FISH detected bcr/abl in 18% of cells
You would recommend:
1.  A bone marrow aspirate for
cytogenetics
2.  Switch to dasatinib or nilotinib
3.  Referral for allogeneic transplantation
4.  Testing for imatinib blood levels
5.  Continuation of imatinib with repeat
FISH in 3 months
Survival Without AP/BC by Level of CyR
at 12 months on First-line Imatinib
~ 2/3 of patients
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
!
• 
Six months later a bone marrow was done
which showed a normal female karyotype.
•  Pcr for bcr/abl did not demonstrate a major
molecular response (0.18% on the
International scale)
You would recommend:
1.  Switch to dasatinib or nilotinib
2.  Referral for allogeneic transplantation
3.  Continuation of imatinib with repeat bone
marrow pcr in 3 months
4.  Continuation of imatinib with peripheral
blood pcr in 3 months
27
0
1.0
2.0
3.0
4.0
5.0
Leukocytosis
13
12
Ph-chromosome pos
11
Ph-negative but..
10
RQ-PCR positive
9
RQ-PCR negative
6.0
8
7
6
5
4
3
2
0
Cure ?
1
0
Number of leukemia cells (log10)
Decreasing residual
leukemia
Log reduction from baseline
BCR-ABL transcript numbers expressed as
log reduction in responding CML patients
HOW TO MONITOR
RESPONSE
•  Marrow with cytogenetics at diagnosis
•  Peripheral blood FISH or serial pcr
every 3 months
•  Marrow to confirm cytogenetic
remission
•  Peripheral blood pcr thereafter
MAJOR MOLECULAR RESPONSE (MMR)
•  Samples from a subgroup of ~ 40 patients
• 
• 
• 
• 
from the IRIS trial were used to establish
an average baseline of transcripts at the
time of diagnosis
It is NOT calculated from the baseline
value in an individual patient
International Scale
– Baseline is 100%
– MMR (3 log reduction) is < 0.1%
– CyCR is ~ 1% (2 log reduction)
Initial analyses suggested an improved
outcome in patients in whom a 3 log
reduction in transcripts was achieved
And it took on a life of it own
But, you have to be able to
measure it…..
CAVEATS
Therefore, reporting BCR-ABL values on the
IS will allow accurate comparison of
response rates for clinical trials,
providing, however, that laboratories
maintain the consistent performance of
their RQ-PCR analytical system. This can
be monitored by the inclusion of QC
samples in every run to recognize shifts
in data, which should be corrected before
results are deemed acceptable.
Otherwise, the laboratory-specific
conversion factor may be invalid.
Branford S et al. Blood 112:3330, 2008
MORE CAVEATS
• 
Furthermore, assessment of precision should ideally be
performed using stable QC samples with defined BCR-ABL
values that are analyzed at least 10 times over several
runs. Such material has currently not been tested and is
not available. Therefore, the procedures used in this study
require refinement to appropriately assess the
performance of each laboratory.
•  Therefore, there will be a need to continue
the conversion factor process for some
time to achieve standardization. This may
be a formidable task for laboratories where BCR
-ABL analysis is a minor component of their testing
procedures.
Branford S et al. Blood 112:3330, 2008.
TECHNICAL ISSUES
•  Duplicate results have more variability
at lower ranges
- CAP survey: ~ 50% of labs perform
duplicates; few report duplicate
values
- pipetting variability
- RNA quality
•  As an example, I frequently see
duplicate results of 0/.001%
•  ~ $550/test
QUANTITATIVE PCR FOR BCR/ABL
•  The test can be fickle with some variability
•  Use the same laboratory for serial
monitoring
•  Never change therapy based on a single
result – repeat in 4-6 weeks
•  If there is a clear-cut pattern of increase:
bone marrow for cytogenetics, bcr/abl
kinase mutational analysis
•  It is very helpful to know what pcr “level”
corresponds to CyCR in your laboratory
PCRITIS
Side effects
Confused physicians
Inappropriate dose increase
Inappropriate referral for transplantation
Inappropriate switch to new TKI
Patient anxiety
38
•  As a CML patient for almost 5 years, and someone who is in
regular contact with other CML patients from around the
world, I continually see the confusion that surrounds this
very important issue. We hang on every PCR test result,…
•  So PCR numbers from different labs cannot be directly
compared. This is a source of confusion when an oncologist
uses different labs, when we change physicians, or when we
see a specialist who uses a different lab.
•  …..her PCRs had been done by different labs, and only the
more recent PCR result was on the International Scale…. But
the oncologist did not understand this change in PCR
methodology and instead of providing a log reduction
comparison simply compared the PCR numbers, and
assumed she was failing drug therapy
•  Other sources of PCR confusion continue unabated.
39
LONG TERM MOLECULAR
MONITORING
•  Know your lab
•  Know which levels in that lab = CCyR
•  Use the same lab for serial samples in
individual patients
•  Repeat the test before changing therapy
•  With few exceptions, it’s a marathon, not a
sprint
If the relapse rate is so low,
why bother to monitor after
the first couple of years??
• It is fun to see these patients
doing so well
• REINFORCE COMPLIANCE!!
• Stop therapy someday??
B. Hanfstein, M. C. Müller, P. Erben, M. Lauseker,
S. Saussele, U. Proetel, S. Schnittger, C. Haferlach,
H. J. Kolb, S. W. Krause, C. Nerl, D. Heim, G. M. Baerlocher,
J. E. A. Schubert, H. Einsele, M. Hänel, J. Dengler, C. Falge,
L. Kanz, A. Neubauer, M. Kneba, F. Stegelmann,
M. Pfreundschuh, C. Waller, M. Pfirrmann, J. Hasford,
W.-K. Hofmann, R. Hehlmann, A. Hochhaus
for the SAKK and the German
CML Study Group
Thank You!
over 200
participating
centers
including
Switzerland and
Czech Republic
Progression-free Survival (PFS)
BCR-ABLIS at 3 months ≤1% vs. 1-10% vs. >10%
≤1%
1-10%
>10%
BCR-ABLIS
n
5Y-PFS
≤1%
218
96%
p-value
1-10%
281
92%
>10%
189
87%
n.s.
0.037
Overall Survival (OS)
BCR-ABLIS at 3 months ≤10% vs. >10%
≤10%
>10%
BCR-ABLIS
n
5Y-OS
p-value
≤10%
501
95%
>10%
191
87%
<0.001
Overall Survival (OS)
BCR-ABLIS at 3 months ≤1% vs. 1-10% vs. >10%
≤1%
1-10%
>10%
BCR-ABLIS
n
5Y-OS
≤1%
218
97%
p-value
1-10%
283
94%
>10%
191
87%
n.s.
0.012
Overall Survival (OS)
Ph+ at 3 months ≤35% vs. >35%
≤35%
>35%
Ph+
n
5Y-OS
p-value
≤35%
336
95%
>35%
124
87%
0.036
(Their) Conclusions
  The levels of molecular or cytogenetic response at 3
months allow for a risk stratification of patients‘
outcome in terms of PFS and OS.
  Missing the 10% BCR-ABLIS landmark at 3 months
predicts inferior survival:
5-year OS with BCR-ABLIS >10% at 3 months is
87% (28% of pts.)
5-year OS with BCR-ABLIS <1% at 3 months is 97%
(31% of pts.)
  Treatment intervention is suggested for slow
responders as indicated by inferior survival.
LESSONS FROM THESE AND THE
OTHER ABSTRACTS INCLUDED IN THE
HANDOUT (and this week’s JCO)
•  Rapid response is predictive of excellent
• 
• 
• 
• 
long term outcome
The OS in “failures” is still very good
It is not known whether switching “early” will
help – poor initial response may be a marker
of overall resistance
Is this supportive of using new TKIs front
line?
New ELN guidelines are being developed
/debated
"Not everything that counts can be
counted, and not everything that can be
counted, counts."
Albert Einstein
Initial Findings from the PACE Trial:
A Pivotal Phase 2 Study of PONATINIB
in Patients with CML and Ph+ ALL
Resistant or Intolerant to Dasatinib or
Nilotinib, or with the T315I Mutation
J Cortes, D-W Kim, J Pinilla, P le Coutre, C Chuah, F Nicolini,
R Paquette, J Apperley, J DiPersio, HJ Khoury, D Rea, M Talpaz,
DJ DeAngelo, E Abruzzese, M Baccarani, MC Mueller,
C Gambacorti-Passerini, S Wong, S Lustgarten, CD Turner, V Rivera,
T Clackson, F Haluska, and HM Kantarjian
On behalf of the PACE Investigators
Ponatinib
• 
Oral pan-BCR ABL TKI with potent activity against
native and mutated BCR-ABL and other kinases
• 
Rationally designed with
extensive network of
optimized molecular
contacts and triple bond to
accommodate T315I
I315 triple bond pona*nib • 
Phase 1 trial
•  Recommended dose: 45 mg/day
•  Well-tolerated
•  Early and durable responses in refractory patients
• 
This is the initial report of the pivotal phase 2 PACE trial
PACE Initial Results
Prior Treatments
N (%)
Prior TKIs
Imatinib only*
CP-CML
R/I
N=207
T315I
N=64
0 (0)
10 (16)
Overall
N=444
16 (4)
Imatinib + (dasatinib OR nilotinib)*
76 (37)
Imatinib + dasatinib + nilotinib*
124 (60) 21 (33) 237 (53)
≥ 2 prior TKIs**
≥ 3 prior TKIs**
31 (48) 172 (39)
98% 83% 94%
66% 41% 59%
Data as of 02 Dec 2011
PACE Initial Results
Best Response to Most Recent
Dasatinib or Nilotinib
% Attaining Endpoint
Endpoint
CP-CML
AP-CML
BP-CML
Ph+ALL
MCyR
(primary CP endpoint)
25%
N/A
N/A
MaHR
(primary AP, BP/ALL endpoint)
N/A
33%
25%
MMR
3%
6%
4%
Data as of 02 Dec 2011
PACE Initial Results
Response CP-CML Cohorts
n Response / N Evaluable (%)
Response
Overall
R/I Cohort
T315I Cohort
CHR
248/271 (92)
193/207 (93)
55/64 (86)
MCyR*
116/248 (47)
79/191 (41)
37/57 (65)
96/248
(39%)
63/191
(33%)
33/57
(58%)
51/265 (19)
31/205 (15)
20/60 (33)
CCyR
MMR
*MCyR is the primary endpoint
Data as of 02 Dec 2011
PACE Initial Results
Response by Mutation Status CP-CML
Mutation Status at Entry
CP-CML
n Response / N Evaluable (%)
MCyR
CCyR
MMR
Any mutation
30/66 (46)
24/66 (36)
16/69 (23)
No mutation
49/125 (39) 40/125 (32) 15/136 (11)
R/I Cohort
T315I Cohort
T315I only
28/43 (65)
24/43 (56)
16/48 (33)
T315I + additional mutation(s)
9/14 (64)
9/14 (64)
4/12 (33)
Data as of 02 Dec 2011
PACE Initial Results
Response Advanced Phase Cohorts
n Response / N Evaluable (%)
Response
AP-CML
R/I
MaHR*
MCyR
31/42
(74)
17/54
(32)
6/54
CCyR
(11%)
MMR
4/59 (7)
BP-CML/Ph+ALL
T315I
R/I
T315I
6/13 (46)
17/46 (37)
16/43 (37)
9/17 (53)
14/41 (34)
15/41 (37)
4/17
(24%)
11/41
(27%)
11/41
(27%)
1/15 (7)
9/41 (22)
2/29 (7)
*MaHR is the primary endpoint (excludes 15 patients with baseline MaHR)
Data as of 02 Dec 2011
PACE Initial Results
Treatment-Related Adverse Events
Treatment-Related Adverse
Events
(≥ 10% any grade)
Rash*
Dry skin
Abdominal pain
Headache
Fatigue
Myalgia
Arthralgia
Lipase increased
Constipation
Nausea
Asthenia
Pancreatitis
Thrombocytopenia
Neutropenia
Anemia
CP-CML (N=271)
Any Grade Grade ≥ 3
n (%)
n (%)
Entire Study (N=449)
Any Grade
Grade ≥ 3
n (%)
n (%)
102 (38)
78 (29)
59 (22)
55 (20)
45 (17)
41 (15)
43 (16)
43 (16)
40 (15)
28 (10)
27 (10)
18 (7)
10 (4)
4 (2)
17 (6)
4 (2)
2 (1)
3 (1)
5 (2)
20 (7)
3 (1)
0 (0)
2 (1)
16 (6)
144 (32)
107 (24)
83 (19)
75 (17)
65 (15)
63 (14)
61 (14)
61 (14)
55 (12)
47 (11)
35 (8)
26 (6)
14 (3)
5 (1)
23 (5)
5 (1)
4 (1)
3 (1)
5 (1)
35 (8)
4 (1)
0 (0)
4 (1)
21 (5)
99 (37)
36 (13)
21 (8)
76 (28)
32 (12)
11 (4)
140 (31)
68 (15)
52 (12)
110 (25)
61 (14)
31 (7)
*Combines the terms erythematous, macular and papular rash
Data as of 02 Dec 2011
What’s next for Ponatinib?
•  NDA for patients refractory/intolerant of
second nilotinib and/or dasatinib with
or without the T315I
•  Consideration of a randomized
comparison with imatinib in newly
diagnosed patients with chronic phase
CML
• 
The pcr for bcr/abl became undetectable.
After 4 additional years of continued
imatinib treatment, it remains negative.
•  The patient would like to become pregnant
You would tell her:
1.  Imatinib is teratogeneic and you counsel
against pregnancy
2.  Relapse is universal after discontinuation of
successful TKI therapy
3.  If relapse occurs after imatinib
discontinuation, reinduction therapy is
usually not successful
4.  You would consider discontinuation with
close monitoring and if it remains negative,
pregnancy could be considered
IMATINIB PACKAGE INSERT
Pregnancy Category D
Women of childbearing potential should be
advised to avoid becoming pregnant while
taking Gleevec. Sexually active female
patients taking Gleevec should use adequate
contraception. Imatinib mesylate was
teratogenic in rats when administered during
organogenesis at doses approximately equal
to the maximum human dose of 800 mg/day.
Discontinuation of Imatinib in
Patients with Chronic Myeloid
Leukemia WHO HAVE
MAINTAINED COMPLETE
MOLECULAR RESPONSE:
Update Results of the STIM
François-Xavier Mahon, Delphine Réa, Joëlle Guilhot, François Guilhot,
Françoise Huguet, Franck Nicolini, Laurence Legros, Aude Charbonnier,
Agnès Guerci, Bruno Varet, Gabriel Etienne, Josy Reiffers, Philippe
Rousselot, on behalf of the Intergroupe Français des Leucémies
Myéloïdes Chroniques (FILMC)
on behalf of the STIM Investigators
‹#›
64
Kaplan-Meier estimates of CMR after
discontinuation of imatinib
The overall probability of maintenance of CMR at 24
and 36 months was 39% (95% CI 29-48).
Molecular relapse occurred in 61 pts with 58 relapses
occurring during the first 7 months -- 3 late relapses at
months 19, 20 and 22
‹#›
65
Fluctuation of BCR-ABL detection
after discontinuation
% BCR-ABL/ABL
10
1
STOP 0.1
0.01
0.001
Among the 39 pts without confirmed molecular relapse,
5 exhibited a fluctuation in BCR-ABL transcript detection
Multivariate Analysis Cox model:
all patients and all relapses
Multivariate analysis
Cox model
Hazard ratio (95% CI)
Sokal score 2.555 (1.278 -5.119)
IM duration
>60 months
vs <60
months
0.582 (0.340 -0.995)
p value
0.008
0.047
Final Model => 2 independent prognostic factors
‹#›
67
Kaplan-Meier estimates of CMR after discontinuation of
imatinib in 100 pts according to combined factors
MANY REMAINING ISSUES
- minimal understanding of non bcr/abl
mutation mechanisms of resistance
- poor outcomes in AP, myeloid BP : new
trials
-  clonal changes in Ph- cells
-  Effect of T/NK proliferation with dasatinib
- are patients “cured” and why?