Chronic Myeloid Leukemia in 2011
Chronic Myeloid Leukemia in 2011
An Update on Treatment and
An Update on Treatment and
Monitoring
Monitoring
Michael Deininger MD PhD Michael Deininger MD PhD
Chief, Division of Hematology and Hematologic Malignancies Chief, Division of Hematology and Hematologic Malignancies
M. M.
M. M. WintrobeWintrobe Professor of MedicineProfessor of Medicine
Concept of leukemia as a disease entity
Leukemia originates from the bone
marrow
1845 1847 1865
Neoplastic nature recognized and term
leukemia coined First published use of arsenic to treat leukemia 1872 1959 Busulfan introduced 1969 1960 Ph chromosome Hydrea introduced 1973 t(9;22) 1968 CML originates in a stem cell 1975 Allotransplant for CML 1985 Interferon-α BCR-ABL 1990 Mouse model reproduces CML; tyrosine kinase activity essential 2001 Imatinib approved 2006 Dasatinib Nilotinib approved
1. Current therapy of CML
2. Prognostic implications of BCR-ABL quantitative PCR
3. International Scale to express BCR-ABL 4. Triggers for additional diagnostic measures
Topics to cover
Chronic phase
Blastic phase
Most CML Patients are Diagnosed
Most CML Patients are Diagnosed
in the Chronic Phase
in the Chronic Phase
9
22 Ph
9q+
The Cytogenetic Hallmark of CML is
the Philadelphia Chromosome (Ph)
22q- = Philadelphia chromosome
Courtesy of Christl Müller, Leipzig
BCR ABL BCR ABL BCR
{
q11 Ph Ph 9q+ 9q+ 22 229
9
{
q34 ABLPh is the result of t(9;22)(q34;q11)
e19a2 b3a2 b2a2 e1a2
BCR-ABL
Ib ABLIa a2a3 a11
BCR
e1 e1’e2’ b2 b3 e19
m-bcr M-bcr µµµµ-bcr
Breakpoints of The Ph Translocation
and BCR-ABL mRNAs
BCR-ABL Kinase Activity Is Essential for
CML Pathogenesis
NALM-1 cells (Ph+) 0.1 0.5 1.0 5.0 10 Imatinib (µM) BCR-ABL-Deininger et al Blood 1997 BCR-ABL K56232D32p2 10BC R-AB L K56232D32p2 10BC R-AB LCML Originates From a BCR
CML Originates From a BCR--ABL
ABL
Transformed Hematopoietic Stem Cell
Transformed Hematopoietic Stem Cell
Red cells CMP GMP Monocytes Granulocytes MEP MKP Platelets CD34+ CD38- Lin- ST-HSC LT-HSC CD34+ CD38+ EB Lin+ BCR-ABL Quintas-Cardama et al, 2006 Imatinib Greatly Improved Survival In Chronic
Therapy Standards
Chronic phase
Advanced phase
Imatinib
Nilotinib
Dasatinib
(IFN)
(Hydrea)
Dasatinib
Nilotinib
Allotransplant
(Imatinib)
(Hydrea)
ABL Kinase Inhibitors
ABL Kinase Inhibitors
DCC-2036 ponatinib DCC-2036 HG-7-85-01 PPY-A (SGX393-like) danusertib
Study Comparison Pts/ Randomization Major endpoints Authors IRIS IM 400mg QD IFN/Ara-C 1106/1:1 PFS O’Brien et al. NEJM 2003 TOPS IM 400mg QD IM 400 BID 476/1:2 MMR at 12 months Cortes et al. JCO 2010 ENESTnd IM 400mg QD NIL 300mg BID NIL 400mg BID 846/1:1:1 MMR at 12 months Saglio et al. NEJM 2010 DASISION IM 400mg QD DAS 100mg QD 519/1:1 CCyR at 12 months Kantarjian et al. NEJM 2010 SPIRIT IM 400mg QD IM 600mg QD IM 400mg QD + IFN IM 400mg QD + AraC 636/1:1:1:1 PFS, OS, EFS Preudhomme et al. NEJM 2010
Tyrosine Kinase Inhibitors For CML:
Major Randomized First Line Studies
Annual Events
Annual Events On First
On First--line
line Imatinib
Imatinib
(IRIS Study
(IRIS Study –– 8 year update)
8 year update)
Deininger et al. ASH 2009
Overall Survival On First
Overall Survival On First--line
line Imatinib
Imatinib
Not All Data Are As Good As The IRIS Data
– Hammersmith Hospital Experience
Hammersmith Hospital Experience
de Lavallade et al. 2008
Event:
Also off IM due to lack of MCyR or toxicity
The Community Experience: Only A Minority Of The Community Experience: Only A Minority Of
Patients Do Well Enough To Remain On IM Patients Do Well Enough To Remain On IM
Lucas et al. Leukemia. 2008 Oct;22(10):1963-6
Study Comparison Pts/ Randomization Major endpoints Authors IRIS IM 400mg QD IFN/Ara-C 1106/1:1 PFS O’Brien et al. NEJM 2003 TOPS IM 400mg QD IM 400 BID 476/1:2 MMR at 12 months Cortes et al. JCO 2010 ENESTnd IM 400mg QD NIL 300mg BID NIL 400mg BID 846/1:1:1 MMR at 12 months Saglio et al. NEJM 2010 DASISION IM 400mg QD DAS 100mg QD 519/1:1 CCyR at 12 months Kantarjian et al. NEJM 2010 SPIRIT IM 400mg QD IM 600mg QD IM 400mg QD + IFN IM 400mg QD + AraC 636/1:1:1:1 PFS, OS, EFS Preudhomme et al. NEJM 2010
Tyrosine Kinase Inhibitors For CML:
Major Randomized First Line Studies
CML: A Chronic Disease Requiring Chronic Therapy CML: A Chronic Disease Requiring Chronic Therapy
0 2 4 6 8 10 12 1998 2000 2002 2004 2006 Prevalence of CML/105
(Pas de Calais Nord, France)
Corm et al, ASCO 2008, #7088
Imatinib cannot be stopped
In 2040 there will be 250,000 CML patients in the US.
ASH 2010 21
ASH 2010 22
DASISION: First-Line Dasatinib vs Imatinib in CML-CP
ASH 2010 23
ASH 2010 25
DASISION: First-Line Dasatinib vs Imatinib in CML-CP
ASH 2010 26
Study Comparison Pts/ Randomization Major endpoints Authors IRIS IM 400mg QD IFN/Ara-C 1106/1:1 PFS O’Brien et al. NEJM 2003 TOPS IM 400mg QD IM 400 BID 476/1:2 MMR at 12 months Cortes et al. JCO 2010 ENESTnd IM 400mg QD NIL 300mg BID NIL 400mg BID 846/1:1:1 MMR at 12 months Saglio et al. NEJM 2010 DASISION IM 400mg QD DAS 100mg QD 519/1:1 CCyR at 12 months Kantarjian et al. NEJM 2010 SPIRIT IM 400mg QD IM 600mg QD IM 400mg QD + IFN IM 400mg QD + AraC 636/1:1:1:1 PFS, OS, EFS Preudhomme et al. NEJM 2010
Tyrosine Kinase Inhibitors For CML:
Major Randomized First Line Studies
ASH 2010 28
DASISION: First-Line Dasatinib vs Imatinib in CML-CP
Primary endpoint Confirmed CCyR by 12 mos
Other key endpoints Rates of CCyR and MMR, times to CCyR and MMR, time in CCyR (measure of duration), progression-free survival, overall survival
Follow-up 5 years Randomized* 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
DASISION (CA180-056) Study Design:
An Ongoing Global Phase 3 Study
ASH 2010 30
DASISION: First-Line Dasatinib vs Imatinib in CML-CP
Based on time-to CCyR analysis, likelihood of achieving a CCyR at any time was 1.5-fold higher with dasatinib than with imatinib (stratified log-rank P<0.0001; HR=1.5)
Among patients who achieved a CCyR, median time to CCyR was 3.1 mos for dasatinib and 5.8 mos for imatinib
CCyR Rates (ITT) By Month Of Treatment
54 73 78 83 85 31 59 67 72 80 0 20 40 60 80 100 Dasatinib 100mg QD Imatinib 400mg QD % Mo 3 Mo 6 Mo 9 Mo 12 Any time ASH 2010 31
DASISION: First-Line Dasatinib vs Imatinib in CML-CP
8 27 39 46 57 13 0.4 8 18 28 41 7 0 20 40 60 80 100 BCR-ABL ≤0.0032% MMR, BCR-ABL≤0.1%
Based on time-to MMR analysis, likelihood of achieving a MMR was 1.8-fold higher with dasatinib vs imatinib (stratified log-rank P<0.0001; HR=1.8) Among patients who achieved a MMR, median time to MMR was 8.3 mos for
dasatinib and 11.8 mos for imatinib
P<0.0001
P=0.0002
MMR Rates (ITT) By Month Of Treatment
Dasatinib 100 mg QD Imatinib 400 mg QD
Mo 3 Mo 6 Mo 9 Mo 12 Any time Any time
ASH 2010 33
DASISION: First-Line Dasatinib vs Imatinib in CML-CP
5 patients who achieved a CCyR transformed to AP/BP CML (2 dasatinib, 3 imatinib) No patient who achieved a MMR transformed to AP/BP CML to date
Patients were followed for transformation for up to 60 days after the last dose of study drug; clonal evolution without additional criteria for AP CML was NOT counted as transformation 2.3 3.5 0 2 4 6 100 n/N 6/259 9/260
Transformation To Advanced Phase CML (ITT)
Dasatinib 100 mg QD Imatinib 400 mg QD %
Monitoring Response: 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
The Need To Confirm Cytogenetic Results
The Need To Confirm Cytogenetic Results
2D Graph 3 X Data 0 20 40 60 80 100 120 Y D a ta -20 0 20 40 60 80 100 120 Col 1 vs Col 2 Col 1 vs Col 3 / 2 ˆ ˆ ˆ pq p z n α ± = ± % P h + m e ta p h a s e s d e te c te d (2 0 a n a ly z e d ) % Ph+ metaphases present 95% CI P =
Byung Park, OHSU
35–65%
50% Ph+ can mean….
Cytogenetics
Cytogenetics vs. BCR
vs. BCR--ABL
ABL qPCR
qPCR
Is There A Role For Peripheral Blood
Is There A Role For Peripheral Blood
FISH For Monitoring Response?
FISH For Monitoring Response?
r = 0.98
Against
IFN-α results not fully confirmed in patients on imatinib
Lack of validation in prospective clinical endpoints
Does not detect clonal evolution
Limited sensitivity and dynamic range compared to qPCR
In Favor
Widely accessible
Excellent correlation with marrow cytogenetics in patients on IFN-α
Le Gouill, S. et al. J Clin Oncol; 18:1533-1538. 2000
FISH only in case of failed cytogenetics or unavailability of qPCR!
IRIS Study: Progression Free Survival by Molecular Response at 12 months on First-line Imatinib
95% 89% 72%
Estimated rate at 54 month
}
p<0.001}
p=0.068
CCyR with >=3 log reduction CCyR with <3 log reduction No CCyR % w it h o u t p ro g re s s io n 0 10 20 30 40 50 60 70 80 90 100
Months since randomization
IRIS
IRIS StudyStudy: : PrognosticPrognostic SignificanceSignificance of Molecular of Molecular Response
Response onon FirstFirst--line line ImatinibImatinib
P=0.014 P=0.0006
P=0.001 P=0.019
Hughes et al. Blood 2010
Lack of MMR at 18 months predicts
Lack of MMR at 18 months predicts
loss of
loss of CCyR
CCyR
Recommendations for Monitoring
Recommendations for Monitoring
Response
Response
Frequency Frequency CBC
CBC Weekly until blood count stableWeekly until blood count stable
Every 4
Every 4--6 (12) weeks thereafter6 (12) weeks thereafter
Cytogenetics
Cytogenetics 3,6, 12, 18 months or until CCyR3,6, 12, 18 months or until CCyR
qPCR
qPCR Every 3Every 3--6 months after 6 months after
documentation of CCyR documentation of CCyR
Therapeutic Milestones
Therapeutic Milestones
Month Optimal Suboptimal Failure
3 <35% Ph+ 36-65%Ph+ No CyR
6 CCyR or
better 1-35% Ph+
66-95% Ph+
12 MMR or better Less than MMR >35% Ph+
18 CMR 0% Ph+ >0% Ph+
Therapeutic Milestones
Therapeutic Milestones
Month Optimal Suboptimal Failure
3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+
Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51
Therapeutic Milestones
Therapeutic Milestones
Month Optimal Suboptimal Failure
3 <35% Ph+ 36-65%Ph+ No CyR
6 CCyR or
better 1-35% Ph+
66-95% Ph+
12 MMR or better Less than MMR >35% Ph+
18 CMR 0% Ph+ >0% Ph+
Therapeutic Milestones
Therapeutic Milestones
Month Optimal Suboptimal Failure
3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+
Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51
Therapeutic Milestones
Therapeutic Milestones
Month Optimal Suboptimal Failure
3 <35% Ph+ 36-65%Ph+ No CyR
6 CCyR or
better 1-35% Ph+
66-95% Ph+
12 MMR or better Less than MMR >35% Ph+
18 CMR 0% Ph+ >0% Ph+
Therapeutic Milestones
Therapeutic Milestones
Month Optimal Suboptimal Failure
3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+
Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51
Therapeutic Milestones
Therapeutic Milestones
Month Optimal Suboptimal Failure
3
Favorable
outcome
likely:
keep going!
Favorable
outcome
uncertain:
consider
alternative!
Favorable
outcome
unlikely:
change
strategy!
6 12 18PCR vs. Cytogenetic Monitoring
PCR vs. Cytogenetic Monitoring
qRT-PCR Cytogenetics Convenience Dynamic Range Sensitivity Standardization Familiarity Additional genetic infoqPCR
qPCR for BCR
for BCR--ABL
ABL –– Lack of
Lack of
Standardization
Standardization
Different technology platforms
Different control genes
Different primers
No uniform standard
Different results reporting
Lack of quality control
US 10 years behind Europe and
Different control genes Different primers/probes Different cycler technologies
Standardization of
Standardization of qPCR
qPCR:
:
The International Scale (IS)
The International Scale (IS)
Courtesy of Dr. Nick Cross, Southhamptom
Reference samples 0.1% 1% 0.01% 10% 0.001% 100% [IRIS baseline] [MMR/3 log reduction]
The International Scale for BCR
The International Scale for BCR--ABL:
ABL:
Before Standardisation
Before Standardisation
B C R B C R --A B L l e v e l A B L l e v e l 0.01 0.1 10 1 0.001 0 CML cell dilution CML cell dilution Lab 1 Lab 2 Lab 3 Lab 4 Lab 5The International Scale for BCR
The International Scale for BCR--ABL:
ABL:
Conversion
Conversion
B C R B C R --A B L l e ve l A B L l e ve l 0.01 0.1 10 1 0.001 0 CML cell dilution CML cell dilution Lab 1 Lab 2 Lab 3 Lab 4 Lab 5 The IS for BCRThe IS for BCR--ABL: Conversion in a Test of a WHOABL: Conversion in a Test of a WHO--approved Reference Standard
approved Reference Standard
Standardization: What Is Achievable?
0.001 0.001 0.1 0.1 1.0 1.0 10 10 0.01 0.01 100 100 0.001 0.001 0.010.01 0.10.1 1.01.0 1010 100100MMR
Courtesy of Dr. Nick Cross, Southhamptom
Standardization: Dependence On Log
Standardization: Dependence On
Log--Linearity Over 0.1
Linearity Over 0.1--10% IS
10% IS
10lo g % B C R -A B L /c on tr ol g e ne 10log dilution 3 0 1 2 10lo g % B C R -A B L /c on tr ol g e ne 10log dilution 3 0 1 2Standardization: What Is Achievable?
CoVar between different labs comparable
to different runs in same lab
Reproducibility within 5-fold above MMR
level?
Uniform results reporting
Uniform reflex triggers for additional
diagnostics
Which increase of BCR
Which increase of BCR--ABL is the right
ABL is the right
trigger for BCR
trigger for BCR--ABL mutation screening?
ABL mutation screening?
10-fold (NCCN guidelines) 5-fold (ELN recommendations)
2-fold (if you live in Australia, Branford et al, Blood 2004)
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)
Sensitivity and Specificity of BCR
Sensitivity and Specificity of BCR--ABL
ABL
Increase for Detection of BCR
Increase for Detection of BCR--ABL Mutations
ABL Mutations
RQ-PCR Increase (fold change) Sensitivity (95% CI) (%) Specificit y (%) Negative Predictive Value (95% CI) (%) Odds Ratio (95% CI) P 2.0 77 (62-88) 44 88 (80-94) 2.6 (1.2-5.4) 0.01 2.5 77 (62-88) 46 89 (81-94) 2.8 (1.4-5.9) 0.005 2.6 77 (62-88) 47 89 (81-94) 2.9 (1.4-6.0) 0.005 2.6* (include subsequent sample) 94 (82-99) 47 97 (91-99) 13 (3.9-43) <0.0001 3.0 74 (60-86) 48 88 (80-94) 2.7 (1.3-5.5) 0.008 3.5 64 (49-77) 54 86 (78-91) 2.1 (1.1-4.1) 0.03 4.0 60 (44-74) 60 85 (78-91) 2.2 (1.1-4.2) 0.02 4.5 55 (40-70) 64 85 (78-90) 2.2 (1.2-4.2) 0.02 5.0 47 (32-62) 68 84 (77-89) 1.9 (1.0-3.6) 0.06 10 26 (14-40) 83 82 (75-87) 1.7 (0.8-3.7) 0.2
Press et al. Blood 2009
Receiver Operating Characteristic Analysis
Receiver Operating Characteristic Analysis
To Define Optimal
To Define Optimal qPCR
qPCR Trigger
Trigger
Summary (1)
Summary (1)
ImatinibImatinib produces durable responses in 2/3 produces durable responses in 2/3 of newly diagnosed chronic phase patients. of newly diagnosed chronic phase patients.
WellWell--established timeestablished time--dependent milestones dependent milestones of response predict outcome.
of response predict outcome.
These milestones are the basis for current These milestones are the basis for current recommendations for monitoring.
recommendations for monitoring.
As the frontline therapy of CML is shifting As the frontline therapy of CML is shifting toward
toward nilotinibnilotinib and and dasatinibdasatinib, they will have , they will have to be adjusted.
to be adjusted.
Summary (2)
Summary (2)
qPCRqPCR monitoring is indicated once a patient monitoring is indicated once a patient has achieved
has achieved CCyRCCyR..
qPCRqPCR is superior to is superior to cytogeneticscytogenetics in terms of in terms of convenience, dynamic range and sensitivity. convenience, dynamic range and sensitivity.
Lack of Lack of qPCRqPCR standardization, low assay standardization, low assay quality and misinterpretation are a frequent quality and misinterpretation are a frequent cause of clinical confusion.
cause of clinical confusion.
Conversion of results allows expression on a Conversion of results allows expression on a uniform scale (IS).