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Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge. Review a downloadable slide deck by Michael W. N. Deininger, MD, PhD, covering the most clinically relevant new data reported from Community Oncology Clinical Debates: Chronic Myelogenous Leukemia. Target Audience This educational activity has been designed to meet the unique learning needs of hematologists, medical oncologists, oncology fellows, and pathologists involved in the treatment of patients with chronic myelogenous leukemia (CML). This program is designed to provide hematologists/oncologists with the latest clinical updates on the treatment of patients with CML in the frontline and relapsed settings. Key elements of this program will highlight many of the clinical challenges faced by physicians as they select appropriate therapeutic regimens for their patients. Assisting clinicians in gaining further perspective regarding the importance of response criteria, clinical monitoring of treatment failure/suboptimal response/disease resistance, timing for switching therapy to obtain maximum therapeutic benefit, the significance of BCR-ABL mutational analysis in patients and how this can assist in selecting therapy and designing individualized approaches to managing CML will be important discussion points throughout the symposium.
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DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is
current as of April 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
Usage RightsUsage RightsThis slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and referencesremain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior writtenpermission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.
DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official
prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestMichael W.N. Deininger, MD, PhDMichael W.N. Deininger, MD, PhD
Reported a financial interest/relationship or affiliation in the form of: Consultant, Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation; Contracted Research, Bristol-Myers Squibb Company, Celgene Corporation, Genzyme, Inc.
Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,
participants should be better able to:participants should be better able to:
Assess patient and disease characteristics for selecting optimal frontline therapies for patients with CML
Identify the characteristics that define a relapsed patient with CML
Evaluate the role of mutational analysis for individualizing therapy choices for patients with CML
Identify investigational agents in clinical development for patients with CML
Activity AgendaActivity Agenda
Activity Overview (5 mins)
Interactive Clinical Debates (50 mins)
– Clinical Debate 1: How Do You Choose the Optimal Frontline Therapy for Patients With CML?
– Clinical Debate 2: How Should the Relapsed/Refractory CML Patient Be Treated?
Questions & Answers (5 mins)
Interactive Clinical DebatesInteractive Clinical Debates
Clinical Debate 1: Clinical Debate 1: How Do You Choose the Optimal How Do You Choose the Optimal
Frontline Therapy for Patients With CML?Frontline Therapy for Patients With CML?
CML: Epidemiology and EtiologyCML: Epidemiology and Etiology In the US, there were 4,870 cases in 2010 and an
expected 5,430 cases in 2012
15% of all adult leukemias
Incidence increases significantly with age
– Median age: ~ 67 years
– Prevalence increasing due to current therapy
– Most patients present in CP
• Majority of CML-related deaths due to progression to AP/BC
– 50% of CML patients are asymptomatic at diagnosis
Risk factors
– Radiation exposure
CML = chronic myeloid leukemia; CP = chronic phase; AP = accelerated phase; BC = blast crisis.NCCN, 2012; Jemal et al, 2010; ACS, 2012; Richardson et al, 2009; Bacarrani, Cortes, et al, 2009.
Chronic Phase Blast Phase
Most CML Patients Are Diagnosed Most CML Patients Are Diagnosed in the Chronic Phasein the Chronic Phase
BCR
ABLABL
BCRABLABL
BCR{q11
PhPh
9q+
2222
99
{q34 ABLABL
Ph Is the Result of t(9;22)(q34;q11)Ph Is the Result of t(9;22)(q34;q11)
Ph = Philadelphia.
9
22
Ph
9q+
The Cytogenetic Hallmark of CML The Cytogenetic Hallmark of CML Is the Philadelphia ChromosomeIs the Philadelphia Chromosome
22q- = Ph chromosome
Courtesy of Christl Müller, Leipzig.
RT-PCR RT-PCR forfor BCR-ABL BCR-ABL
RT-PCR for BCR-ABL in CML
1) Qualitative RT-PCR allows for the diagnosis of CML
2) Quantitative RT-PCR is used to quantify the amount of disease
3) Allows for the identification of cryptic BCR-ABL translocations
4) Does not require a bone marrow aspirate for optimal results
RT-PCR = real time polymerase chain reaction.Suh et al, 2000; Menif et al, 2009; Adapted from Rollins et al, 2000.
Cycle 1 yields 2
molecules
Cycle 2 yields 4
molecules
Cycle 3 yields 8 molecules; 2 molecules
(in white boxes)
match target sequence
Denaturation: Heat briefly to separate DNA strands
Annealing: Cool to allow primersto form hydrogen bond with ends of target sequence
2
1
Extension: DNA polymerase adds nucleotides to the 3” end of each primer
3New nucleo-tides
Primers
Target sequence
Monitoring Response: Monitoring Response: Sensitivity of Strategies Sensitivity of Strategies
Complete Hematologic Response
Diagnosis: 1012 Leukemia Cells
Cytogenetics
Blood Counts
PCR
Undetectable Range
Complete Cytogenetic Response
Major Molecular Response
100%
10%
1%
0.1%
Complete Molecular Response
4.5 log = 0.0032%
BCR-ABL Kinase Activity Is BCR-ABL Kinase Activity Is Essential for CML PathogenesisEssential for CML Pathogenesis
NALM-1 cells (Ph+)
0.1 0.5 1.0 5.0 10
Imatinib (M)
BCR-ABL-
Deininger et al, 1997.
BCR-ABL
K56232D
32p210 BCR-A
BL
MDACC = The University of Texas M. D. Anderson Cancer Center.Quintas-Cardama & Cortes, 2006.
Imatinib Greatly Improved SurvivalImatinib Greatly Improved Survivalin CML-CP (MDACC data)in CML-CP (MDACC data)
Case Study 1Case Study 1
A 60-year-old man presents to his PCP with a history of left-sided abdominal pain, poor appetite, and loss of 10 kg of body weight
PMH is significant for interstitial lung disease with right heart failure and recurrent pleural effusions. A recent EKG shows a QTc interval of 433 ms.
Physical exam reveals splenomegaly (14 cm under left rib cage)
PCP = primary care physician; PMH = past medical history; EKG = electrocardiogram.
Laboratory FindingsLaboratory Findings
HGB 10.1 g/dL, WBC 321/nL, platelets 810/nL
Diff: 25% segs, 23% bands, 17% myelocytes, 10% promyelocytes, 8% basophils,6% monocytes, 4% lymphocytes, 9% blasts
Bone marrow: 7% blasts, 5% basophils
Cytogenetics: 46XY,t(9;22)[20]
HGB = hemoglobin; WBC = white blood count; Diff = differentials; segs = segmented neutrophils.
Case Study 1: Question 1Case Study 1: Question 1
Which diagnostic tests would you add?
1) FISH for BCR-ABL
2) BCR-ABL mutation screening
3) CT abdomen/pelvis ± contrast
4) None of the above
5) All of the above
FISH = fluorescent in situ hybridization; CT = computed tomography.
Case Study 1: Question 2Case Study 1: Question 2
Which information is not important for decision-making?
1) Spleen 14 cm
2) WBC 321/nL
3) PLTs 810/nL
4) Peripheral blood blasts 9%
5) History of pleural effusions
PLTs = platelets.
Case Study 1: Question 3Case Study 1: Question 3
Which of the following are acceptable therapeutic choices?
1) Imatinib 400 mg QD
2) Imatinib 400 mg BID
3) Nilotinib 300 mg BID
4) Dasatinib 100 mg QD
5) Only 1, 2, and 3
6) Only 1, 3
7) Only 1, 3, and 4
NCCN, 2012; Sprycel® prescribing information, 2010; Tasigna® prescribing information, 2011; Gleevec® prescribing information, 2010.
Case Study 1: Question 4Case Study 1: Question 4The patient is started on nilotinib 300 mg BID.
Which two statements about monitoring this patientare incorrect?
1) Blood counts should be monitored weekly until stable
2) Monitoring transaminases and lipase is unnecessary
3) A BMB and karyotyping at 3 months are standard of care
4) Once a complete cytogenetic response has been documented monitoring continues with qPCR only
5) Annual BMB should continue indefinitely
BMB = bone marrow biopsy.
Getting Things Right at DiagnosisGetting Things Right at Diagnosis
History and physical exam: Record spleen size in cm below costal margin Complete blood count Bone marrow aspirate with marrow differential Conventional cytogenetics Do not treat leukocytosis with imatinib!
The Bare Minimum
Bone marrow trephine FISH for BCR-ABL Diagnostic PCR for BCR-ABL Flow cytometry
Optional
Mandatory in case of Ph-negative karyotype
NCCN, 2012.
Getting Things Right at Diagnosis Getting Things Right at Diagnosis (cont.)(cont.)
Low risk < 0.8
Intermediate risk 0.8–1.2
High risk > 1.2
Establish Disease Phase PLT < 100 Blood or marrow blasts > 15% Basophils > 20% Blasts and promyelocytes > 30% Blasts > 30%
Establish Sokal Risk Score = Exp [0.0116 (Age – 4.34)] + 0.0345 (Spleen – 7.51) + 0.188 [(PLT/700)2 – 0.563] + 0.0887 (PB blasts – 2.1)
NCCN, 2012.
New CML Risk Score (Eutos Score) for New CML Risk Score (Eutos Score) for Patients Treated With ImatinibPatients Treated With Imatinib
PFS = progression-free survival.Hasford et al, 2011.
Eutos Score = (7 x basophils) + (4 x spleen size)
High risk: > 87Low risk: ≤ 87
Requires Confirmation
PFS
Is There A Role for Peripheral Blood Is There A Role for Peripheral Blood FISH for Monitoring Response?FISH for Monitoring Response?
Good correlation between BM, FISH, and karyotyping
CBA = chromosome banding analysis; CCgR = complete cytogenetic response; I-FISH = interphase fluorescence in situ hybridization; PCgR = partial cytogenetic response.Testoni et al, 2009.
Distribution of I-FISH Data According to CBA Data
Cytogenetic response by I-FISH, n (%)
Cytogenetic response by CBA < 1% BCR-ABL+ nuclei
1%–5% BCR-ABL+ nuclei
> 5% BCR-ABL + nuclei
CCgR (n = 537), no Ph+ metaphases 444 (82.7) 71 (13.2) 22 (4.1)
PCgR (n = 77), 1%–35% Ph+ metaphases 7 (9.1) 32 (41.6) 38 (49.3)
p Value < .001 < .001 < .001
Is There A Role for Peripheral Blood Is There A Role for Peripheral Blood FISH for Monitoring Response? (cont.)FISH for Monitoring Response? (cont.)
In Favor
Wide accessibility Excellent correlation with marrow
cytogenetics in patients on IFN-α
r = 0.98
Against
IFN-α results not validated in patients on imatinib Not validated prospectively with clinical end points Does not detect clonal evolution Limited sensitivity and dynamic range compared to qPCR
IFN = interferon.Le Gouill et al, 2000.
% Ph +
100
80
60
40
20
0
0 20 40 60 80 100 % Ph +
Therapy StandardsTherapy Standards
Chronic Phase Imatinib
Nilotinib
Dasatinib
(IFN-α)
(Hydroxyurea)
Advanced Phase Dasatinib
Nilotinib
Allotransplant
(Imatinib)
(Hydroxyurea)
NCCN, 2012.
Study Comparison Patients / Randomization
Major End Points
Author
IRIS IM 400 mg QD IFN / Ara-C
1,106 / 1:1 PFS O’Brien et al, 2003
TOPS IM 400 mg QD
IM 400 BID
476 / 1:2 MMR at 12 months
Cortes et al, 2010
ENESTnd IM 400 mg QD NIL 300 mg BID NIL 400 mg BID
846 / 1:1:1 MMR at 12 months
Saglio et al, 2010
DASISION IM 400 mg QD DAS 100 mg QD
519 / 1:1 CCyR at 12 months
Kantarjian et al, 2010
Choosing a TKI for First-Line TherapyChoosing a TKI for First-Line Therapy
TKI = tyrosine kinase inhibitor; IM = imatinib; NIL = nilotinib; DAS = dasatinib; MMR = major molecular response; CCyR = complete cytogenetic response.
OS = overall survival.Deininger et al, 2009.
OS on First-Line Imatinib OS on First-Line Imatinib (IRIS Study)(IRIS Study)
CCyR with >=3 log reductionCCyR with <3 log reductionNo CCyR
% w
ithou
t pro
gres
sion
0
10
20
30
40
50
60
70
80
90
100
Months since randomization0 6 12 18 24 30 36 42 48 54 60
IRIS Study: PFS by Molecular Response IRIS Study: PFS by Molecular Response at 12 Months on First-Line Imatinib at 12 Months on First-Line Imatinib
95% 89% 72%
Estimated Rate at 54 Months
} p < .001} p = .068
Deininger et al, 2009.
CCyR with ≥ 3 log reductionCCyR with < 3 log reductionNo CCyR
IRIS Study 7-Year Follow-Up: Prognostic Significance IRIS Study 7-Year Follow-Up: Prognostic Significance of Molecular Response on First-Line Imatinib of Molecular Response on First-Line Imatinib
p = .014 p = .0006
P=0.001p = .019
Hughes et al, 2010.
Not All Data Are As Good As IRIS Data: Not All Data Are As Good As IRIS Data: Hammersmith Hospital ExperienceHammersmith Hospital Experience
CHR = complete hematologic response; EFS = event-free survival; MCyR = major cytogenetic response.de Lavallade et al, 2008.
Event: Also off IM due to lack of MCyR or toxicity
63%
The Community Experience: Only A Minority The Community Experience: Only A Minority of Patients Do Well Enough to Remain on IMof Patients Do Well Enough to Remain on IM
CCRe = complete cytogenetic response equivalence.Lucas et al, 2008.
TOPS 24-Mos Update: Study DesignTOPS 24-Mos Update: Study Design
PFS, OS
Imatinib 400 mg/day (n = 157)
Imatinib 800 mg/day (400 mg BID; n = 319)
MMR* at 12 months
2:1 randomization
N = 476
Total 5 years (planned)
Data cut-off of December 31, 2008.*BCR-ABL/control gene ≤ 0.1% utilizing the International Scale.
Patients enrolled at 103 sites in 19 countries, first patient first visit June 2005 Cytogenetic analysis every 6 months until CCyR, then every 12 months Molecular analysis by PCR every month for Months 1–3, then every 3 months
TOPS = Tyrosine Kinase Inhibitor Optimization and Selectivity.Cortes, Baccarani, et al, 2010.
TOPS Trial: Imatinib 400 mg Vs. 800 mg: TOPS Trial: Imatinib 400 mg Vs. 800 mg: MMR Rates Over Time (ITT)MMR Rates Over Time (ITT)
ITT = intent to treat.Cortes, Baccarani, et al, 2010.
Impact of Dose Intensity* on Cumulative Impact of Dose Intensity* on Cumulative CCyR Rates, 800 mg ArmCCyR Rates, 800 mg Arm
% P
atie
nts
Ach
ievi
ng
CC
yR
p = .001
800 mg Arm800 mg Arm
*Dose intensity (total amount of drug received divided by the number of days on treatment including days of zero dose) in the first 12 months of treatment.
p = .510
Cortes, Baccarani, et al, 2010.
Event-Free Survival* (ITT)Event-Free Survival* (ITT)
400 mg
800 mg
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42
% P
atie
nts
With
out
Eve
nt
Months Since Randomization
EFS at 24 Months95% for Both Arms
*EFS; time between randomization and death, progression to AP/BC, loss of MCyR [Ph+ bone marrow cells > 35%] or loss of CHR.
Baccarani et al, 2009.
Nilotinib in CP1 First-Line: Nilotinib in CP1 First-Line: 3-Year Update of ENESTnd3-Year Update of ENESTnd
Saglio et al, 2011.
Primary end point: MMR at 12 months
Patient DispositionPatient Disposition
Few patients discontinued treatment since the 2-year follow-up
– 4% on nilotinib 300 mg BID; 5% on nilotinib 400 mg BID; 6% on imatinib
Saglio et al, 2011.
% W
ith
MM
R
33
Months Since Randomization
73%, p < .0001
70%, p < .0001
53%
By 3 Years
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30
55%, p < .0001
51%, p < .0001
27%
By 1 Year
Δ 24%–28%
Δ 17%–20%
Nilotinib 300 mg bid
Nilotinib 400 mg bid
Imatinib 400 mg qd
282
281
283
n
36
Cumulative Incidence of MMRCumulative Incidence of MMR
Saglio et al, 2011.
Patients With High Sokal Risk Have the Patients With High Sokal Risk Have the Largest Improvement of MMR by 3 YearsLargest Improvement of MMR by 3 Years
77 7567
63
54
39
0
10
20
30
40
50
60
70
80
Low Intermediate High
Nilotinib 300 mg BID Imatinib 400 mg QD
% W
ith
MM
R
n = 103 104 101 101 78 78
p = .0264 p = .0020p = .0004
Δ 14% Δ 21% Δ 28%
Saglio et al, 2011.
Nilotinib 300 mg bid
Nilotinib 400 mg bid
Imatinib 400 mg qd
282
281
283
n
% W
ith
MR
4.5
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33
11%, p < .0001
7%, p < .0001
1%
By 1 Year
Δ 6%–10%
36
32%, p < .0001
28%, p = .0003
15%
By 3 Years
Δ 13%–17%
Months Since Randomization
Cumulative Incidence of CMRCumulative Incidence of CMR
26%
21%
10%
By 2 Years
Saglio et al, 2011.
Progression to AP/BC: Including Events Progression to AP/BC: Including Events After Discontinuation (ITT Analysis)After Discontinuation (ITT Analysis)
Nu
mb
er o
f P
atie
nts
(n
)
On Core Treatment and After Discontinuation
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
96
19p = .0496
p = .0076
Off treatment progression information was prospectively collected for all patients every 3 months after discontinuation
HR = 0.5 [0.2, 1.0]HR = 0.3 [0.1, 0.8]
3.2% 2.1% 6.7%
HR = hazard ratio.Saglio et al, 2011.
Survival After Progression to AP/BCSurvival After Progression to AP/BC%
Ali
ve
Months Since Progression
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36
Median Survival 10.5 months
Progressed = 34Died = 23Alive = 11
Saglio et al, 2011.
Overall Survival Overall Survival
Of 38 total deaths on study, 23 were following progression to AP/BC
CI = confidence interval.Saglio et al, 2011.
Dasatinib in CP1 First-Line Dasatinib in CP1 First-Line 2-Year Update of 2-Year Update of
DASISIONDASISION
Primary end point Confirmed CCyR by 12 months
Other key end points Rates of CCyR and MMR, times to CCyR and MMR, time in CCyR (measure of duration), PFS, OS
Follow-up
5 yearsRandomized*
Imatinib 400 mg QD (N = 260)
Dasatinib 100 mg QD (N = 259) Treatment-naïve
CML-CP patients
(N = 519)
108 centers
26 countries*Stratified by Hasford risk score
Hochhaus et al, 2011.
Cumulative Incidence of MMRCumulative Incidence of MMR
Months
100
80
60
40
20
0
Dasatinib 100 mg QD
Imatinib 400 mg QD
0 3 6 9 12 15 18 21 24 27
65%
47%
47%
28%
Δ 19%
Δ 18%
Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.
% o
f P
atie
nts
By 24 monthsBy 12 months
Hochhaus et al, 2011.
Cumulative Incidence of CMRCumulative Incidence of CMR
Dasatinib 100 mg QD
Imatinib 400 mg QD
0 3 6 9 12 15 18 21 24 27
100
80
60
40
20
0
By 24 months17%
9%
Months
Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.
% o
f P
atie
nts
Hochhaus et al, 2011.
BCR-ABL Levels at 3 Months*BCR-ABL Levels at 3 Months*
0
20
40
60
80
100
84%
64%
16%
36%
% o
f P
atie
nts
BCR-ABL Level at 3 Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
n/N 198/235 154/239 37/235 85/239
≤ 10% > 10%
*Calculated from total number of evaluable patients with PCR assessments at 3 months.
> 1–10%
≤ 1%
> 1–10%
≤ 1%
Hochhaus et al, 2011.
Cumulative Incidence of CCyR Within 24 Months Cumulative Incidence of CCyR Within 24 Months According to BCR-ABL Level at 3 MonthsAccording to BCR-ABL Level at 3 Months
0 6 12 18 24 30
0 6 12 18 24 30Months Months
% C
CyR
% C
CyR
Dasatinib 100 mg QD Imatinib 400 mg QD
≤ 1% > 1–10% > 10%
BCR-ABL at 3 months
100
80
60
40
20
0
100
80
60
40
20
0
98%
38%
64%
98%100%94%
24 months 24 months
Hochhaus et al, 2011.
Transformation to AP/BP According to Transformation to AP/BP According to BCR-ABL Level at 3 MonthsBCR-ABL Level at 3 Months
0
2
4
6
8
10
Total
% T
rans
form
atio
n
Dasatinib 100 mg QD
Imatinib 400 mg QD
2.6%
> 10%
5.0%
≤ 1%
1.8%
0%
1.2%
9.4%
BCR-ABL Level at 3 Months
n/N 6/235 12/239 2/112 0/32 1/86 4/122 3/37 8/85
3.3%
8.1%
> 1–10%
Hochhaus et al, 2011.
OS According to BCR-ABL Level OS According to BCR-ABL Level at 3 Months at 3 Months
% A
live
% A
live
≤ 1%> 1–10%> 10%
Months
BCR-ABL Level at 3 months
≤ 1%> 1–10%> 10%
BCR-ABL Level at 3 months
Dasatinib 100 mg QD Imatinib 400 mg QD
100
80
60
40
20
00 6 12 18 24 30 36 42
Months0 6 12 18 24 30 36 42
100
80
60
40
20
0
For ≤ 10% vs. > 10% comparison: p = .0137 For ≤ 10% vs. > 10% comparison: p = .0081
Hochhaus et al, 2011.
Nilotinib and Dasatinib Are Better Nilotinib and Dasatinib Are Better Tolerated Than ImatinibTolerated Than Imatinib
Nilotinib / Dasatinib Better
NIL DASIM IM
Nausea
Saglio et al, 2011; Hochhaus et al, 2011.
ENESTnd Vs. DASISION ENESTnd Vs. DASISION Communalities
– Superiority of experimental arm in terms of primary end point
– Equal or better tolerability of experimental arm
– High drop out rates
– No difference in OS
ENESTnd DASISION
Risk stratification Sokal Hasford
Dose escalation in experimental arm
No Yes
Assessment of progression On therapy Up to 60 days post d/c of therapy
Differences in Design
d/c = discontinuation.Larson et al, 2011; Kantarjian et al, 2011.
ENESTnd Vs. DASISION ENESTnd Vs. DASISION An Unallowed ComparisonAn Unallowed Comparison
ENESTnd DASISIONCCyR 24 months (%) 87/85a 86a
MMR 24 months (%) 62/59b 64a
PFS superior in experimental arm Yes No
Assessment of progression On therapyUp to 60 days post d/c
of therapy
aResponse by time point.bResponse at time point.Larson et al, 2011; Kantarjian et al, 2011.
SO325 Trial DesignSO325 Trial Design Randomization
– Imatinib 400 mg/d vs. dasatinib 100 mg/d
Stratification
– Hasford risk category: Low vs. intermediate vs. high
Number of patients
– N = 240 (120/arm)
Assessment schedule
– Molecular and hematologic response: 3, 6, 9, 12 mos
– Cytogenetic response: 6, 12 mos
Radich et al, 2010.
BCR-ABL mRNA LevelBCR-ABL mRNA Level
Radich et al, 2010.
Median BCR-ABL reduction: Dasatinib 3.3 log vs. imatinib 2.8 log, p = .048
Clinical Debate 2: Clinical Debate 2: How Should the Relapsed/Refractory How Should the Relapsed/Refractory
CML Patient Be Treated?CML Patient Be Treated?
Case Study 2Case Study 2
A 49-year-old man with CML has been on imatinib 400 mg daily for 7 years
He was diagnosed in chronic phase and achieved CCyR after 6 months
His qPCR levels on the international scale have fluctuated between 0.09% and 0.4%, but the most recent test showed an increase to 5.6%
Comorbidities include diabetes mellitus, polyarthritis, and depression, for which he is managed by 3 additional specialists
He is asymptomatic and physical exam is negative
Case Study 2: Question 1Case Study 2: Question 1
Which are the appropriate next steps?
1) Thorough ‘questioning’ for non-compliance
2) Thorough review of co-medications
3) Repeat qPCR
4) Bone marrow biopsy
5) Imatinib drug level testing
6) All of the above
7) Only 1, 2, and 3
8) Only 1, 2, 3, and 5
Case Study 2: Question 2Case Study 2: Question 2A thorough history reveals no evidence for non-compliance and there was no recent change in medications. The repeat PCR test reveals a level of 7.2IS.
What is your next step?
1) Bone marrow biopsy with cytogenetics
2) Screening for BCR-ABL kinase domain mutations on a blood sample
3) Screening for BCR-ABL kinase domain mutations on a bone marrow sample
4) Only 1, 2, and 3
5) Only 1 and 2
Case Study 2: Question 3Case Study 2: Question 3You receive the following results:
Normocellular marrow with micromegakaryocytes, 2% blasts
Mutation screening positive for F359V BCR-ABL mutation
Cytogenetics 46XY[15]/46XY,t(9;22),inv(3)[5]
What is your next step?
1) Increase imatinib to 800 mg BID
2) Switch to nilotinib 400 mg BID
3) Switch to dasatinib 140 mg QD
4) Evaluate for allotransplant
5) Only 2 and 4
6) Only 3 and 4
Resistance Work-UpResistance Work-Up
Failure to reach milestones or loss of response
NCCN, 2012.
Complete Diagnostic Work-Up Physical exam BMB Karyotyping BCR-ABL mutation screen
No
When Is BCR-ABL Mutation When Is BCR-ABL Mutation Analysis Indicated?Analysis Indicated?
Failure to reach milestones Loss of response, progression
Controversial Routine at diagnosis in patients with AP/BC? Routine monitoring in high-risk patients? Which is the optimal technology? Which is the right qPCR trigger?
Universally Accepted
NCCN, 2012.
Which Increase of BCR-ABL Is the Right Which Increase of BCR-ABL Is the Right Trigger for BCR-ABL Mutation Screening?Trigger for BCR-ABL Mutation Screening?
NCCN guidelines: 10-fold ELN recommendations: 5-fold If you live in Australia: 2-fold
More than 2-fold rise Stable or decreasing
Mutations (%)
resistance (%)
34/56 (61)
31/34 (91)
1/158 (0.6)
1/1 (100)
No mutations (%)
resistance (%)
22/56 (39)
13/22 (59)
157/158 (99)
1/157 (0.6)
Brandford et al, 2004.
Receiver Operating Characteristic Analysis Receiver Operating Characteristic Analysis to Define Optimal qPCR Triggerto Define Optimal qPCR Trigger
Press et al, 2009.
Jmax (2.6-fold)
0 10 20 30 40 50 60 70 80 90 100
1 – Specificity (%)
Sen
siti
vity
(%
)100
90
80
70
60
50
40
30
20
10
0
What Are the Non-Transplant What Are the Non-Transplant Options for Patients With Relapse? Options for Patients With Relapse?
(Imatinib dose escalation)
Nilotinib
Dasatinib
Experimental agents
NCCN, 2012.
Dasatinib: PFS and OS in CML-CP Dasatinib: PFS and OS in CML-CP After IM FailureAfter IM Failure
Months
100
80
60
40
20
0
24 months12 months
91%
PFS
80%387N
24 months12 months
97%
OS
94%387N
% o
f P
atie
nts
0 3 6 9 12 15 18 21 24 27 30 33
Stone et al, 2007.
Nilotinib: PFS and OS in CML-CP Nilotinib: PFS and OS in CML-CP After IM FailureAfter IM Failure
Months Since Start of Treatment
% A
live
Adapted from Kantarjian et al, 2007.
Patients With Cytogenetic Response to Patients With Cytogenetic Response to Second-Line TKIs at 3 Months Do Well Second-Line TKIs at 3 Months Do Well
Proportions of patients ultimately achieving 12 MMCyR
Tam et al, 2008.
Months From 12-Month Landmark
Pro
po
rtio
n A
live
(%
)
Time point, response n 12 MMCyR, no. (%)
3 months
Minor cytogenetic 15 10 (67)
Complete hematologic response or hematologic failure
42 3 (7)
6 months
Minor cytogenetic 16 8 (50)
Complete hematologic response or hematologic failure
39 1 (3)
Blast Crisis: PFS on DasatinibBlast Crisis: PFS on Dasatinib%
No
t P
rog
ress
ed
100
80
60
40
20
0
Months0 3 6 9 12 15 18 21 24 27 30
Lymphoid Blast
Myeloid Blast
Gambacorti et al, 2007.
Dasatinib for IM Failure in CP: Frequency of Baseline Dasatinib for IM Failure in CP: Frequency of Baseline BCR-ABL Mutations by In Vitro ICBCR-ABL Mutations by In Vitro IC5050 to Dasatinib to Dasatinib
IC50 ≤ 3 nM (n = 248)
M244V, G250E, Y253F/H/K, F311L, M351T, E355G, F359C/I/V, V379I, L387M, H396P/R
Unknown IC50 to dasatinib (n = 74)38 different BCR-ABL mutations
No BCR-ABLmutation(n = 421)
52%
IC50 > 3 nM(n = 42)
5%
2% T315I (n = 20) IC50 > 200 nM
1% Q252H (n = 6)
2% F317L (n = 13)
< 1% V299L (n = 1)
3% E255K/V (n = 25)
31%
9%
Patients with resistance or suboptimal response to imatinib
Müller et al, 2008.
Response Rates by In Vitro IC50 to Response Rates by In Vitro IC50 to Dasatinib (excluding T315I)Dasatinib (excluding T315I)
96
73
54
43
94
58
47
34
82
34
2518
0
20
40
60
80
100
CHR MCyR CCyR MMR
Unknown (n=83)
≤3 nM (n=254)
>3 nM (n=44)
IC50 to dasatinib
%
Müller et al, 2008.
Nilotinib Efficacy According to Nilotinib Efficacy According to Baseline BCR-ABL Mutations in CML-CPBaseline BCR-ABL Mutations in CML-CP
Baseline Mutations in Imatinib-Resistant Patients (N = 202)
IC50-based grouping
IC50 ≤ 150 nM M244V, L248V, G250E,
Q252H, E275K, D276G, F317L, M351T, E355A, E355G, L387F, F486S
IC50 > 150 nM Y253H, E255K/V,
F359C/V
IC50 > 10,000 nM T315I
*Mutations without available IC50 data.
45%
24%
4%
4%
15%
5%
3%
No Mutation
IC50 ≤ 150 nM
Y253H
E255K/V
F359C/V
T315I
Others*
Hughes et al, 2009.
O’Hare et al, 2007.
The The ““DefaultDefault”” Mutant T315I Is Resistant to Mutant T315I Is Resistant to All Currently Approved BCR-ABL TKIsAll Currently Approved BCR-ABL TKIs
NCCN Guidelines: NCCN Guidelines: Treatment Options Based on BCR-ABL Treatment Options Based on BCR-ABL
Kinase Domain Mutation StatusKinase Domain Mutation Status
BCR-ABL KD Mutation Treatment Recommendation
T315I HSCT or clinical trial
V299L, T315A, F317L/V/I/C Consider nilotinib rather than dasatinib
Y253H, E255K/V, F359V/C/I
Consider dasatinib rather than nilotinib
Any other mutation Consider high dose imatinib or dasatinib or nilotinib
NCCN, 2012.
Drug Therapy Options for Patients With Drug Therapy Options for Patients With Failure on Second-Line TKI TreatmentFailure on Second-Line TKI Treatment
Third generation ABL kinase inhibitors
– Ponatinib
– Bosutinib
– DCC-2036
Non-targeted agents
– Omacetaxine
Inhibitors of other pathways
– Hedgehog/SMO inhibitors
– Beta-catenin inhibitors
National CML Society, 2011; Hu et al, 2009; Jagani et al, 2010; NCCN, 2012.
Ponatinib (AP24534): Binding to ABLPonatinib (AP24534): Binding to ABLT315IT315I
AP24534
Imatinib
T315I
N
N
O
ONH
N NF3C
H2N
OHAP24534
O’Hare et al, 2009, 2011.
T315I 11 > 3,125 > 200 > 2,000
BCR-ABLCellular Proliferation – IC50 (nM)
AP24534 Imatinib Dasatinib NilotinibNative 0.5 224 0.8 13
Treatment-Emergent AEs (≥ 20% any grade)
N (%; N = 74)
Any Grade ≥ Grade 3
Fatigue 26 (35) 0 (0)Constipation 25 (34) 0 (0)Rash 25 (34) 1 (1)Headache 24 (32) 0 (0)Arthralgia 23 (31) 2 (3)Nausea 22 (30) 0 (0)Abdominal pain 20 (27) 3 (4)Pyrexia 17 (23) 2 (3)Muscle spasms 16 (22) 0 (0)Vomiting 16 (22) 0 (0)Thrombocytopenia 20 (27) 15 (20)Neutropenia 10 (14) 6 (8)Anemia 14 (19) 6 (8)
Data October 15, 2010
Phase I Study of Ponatinib: Phase I Study of Ponatinib: SafetySafety
DLT: Pancreatitis
DLT = dose-limiting toxicity.Cortes et al, 2010.
Response to Ponatinib Response to Ponatinib
Best Response to CML-CP
N (%; 55 evaluable)
Overall
(N = 38)
T315I*
(N = 9)
Non-T315I
(N = 29)
Hematologic
CHR** 36 (95) 9 (100) 27 (93)
Cytogenetic
MCyR 25 (66) 9 (100) 16 (55)
CCyR 20 (53) 8 (89) 12 (41)
Data October 15, 2010
Cortes et al, 2010.
Best Response to CML-AP
N (%; 55 evaluable)
Overall
(N = 17)
T315I*
(N = 5)
Non-T315I
(N = 12)
Hematologic
MHR 6 (35) 1 (20) 5 (42)
Cytogenetic
MCyR 4 (24) 1 (20) 3 (25)
CCyR 2 (12) 0 (0) 2 (17)
*Includes only those with T315I status confirmed at study entry.
T315I detection in the context of TKI failure
Determine disease phase
CP AP/BC
Investigational agent
Tx candidate
Allograft in remission
Treatment Approach for T315I Detection Treatment Approach for T315I Detection and TKI Failureand TKI Failure
NCCN, 2012.
No Tx candidate
Evaluate for allograft
Chemotherapy or IA
Survival After Allogeneic Transplant Survival After Allogeneic Transplant in Patients With Imatinib Failurein Patients With Imatinib Failure
Saussele et al, 2010.
Key TakeawaysKey Takeaways Imatinib, nilotinib, and dasatinib are all approved options for
frontline therapy
Nilotinib and dasatinib are superior to imatinib in newly diagnosed CML-CP in surrogate end point (CCyR; MMR; CMR)
Improved PFS (statistically significant for nilotinib)
Longer follow-up required to ascertain positive effect on OS
Good monitoring starts with complete staging at diagnosis
Milestones define responses as optimal, suboptimal, or failure and are dependent on the type of therapy (will be updated for new TKIs)
Key Takeaways (cont.)Key Takeaways (cont.)
Treatment recommendations are outlined in the NCCN guidelines for specific BCR-ABL kinase domain mutations (eg, dasatinib for F359V/C/I mutations). However:
– Ponatinib is the most promising salvage therapy option for patients who failed second-line TKIs, including those with the T315I mutation
Allotransplant remains an important salvage option and is a mandatory consideration in case of progression to AP/BC
The following targeted agents are options for patients who fail second-line TKIs: Ponatinib, bosutinib, DCC-2036