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A Time Line Of Chronic Myeloid Leukemia

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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

(2)

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

(3)

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 22

9

9

{

q34 ABL

Ph is the result of t(9;22)(q34;q11)

(4)

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 L
(5)

CML 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

(6)

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

(7)

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)

(8)

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

(9)

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

(10)

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

(11)

ASH 2010 22

DASISION: First-Line Dasatinib vs Imatinib in CML-CP

ASH 2010 23

(12)

ASH 2010 25

DASISION: First-Line Dasatinib vs Imatinib in CML-CP

ASH 2010 26

(13)

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

(14)

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-ABL0.1%

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

(15)

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

(16)

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

(17)

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

(18)

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

(19)

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+

(20)

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+

(21)

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+

(22)

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 18
(23)

PCR vs. Cytogenetic Monitoring

PCR vs. Cytogenetic Monitoring

qRT-PCR Cytogenetics Convenience Dynamic Range Sensitivity Standardization Familiarity Additional genetic info

qPCR

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

(24)

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 5
(25)

The 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 BCR

The IS for BCR--ABL: Conversion in a Test of a WHOABL: Conversion in a Test of a WHO--approved Reference Standard

approved Reference Standard

(26)

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 100100

MMR

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 2
(27)

Standardization: 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)

(28)

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

(29)

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).

References

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