current monitoring for cml: goals and principles monitoring webinar with dr. jorge cortes.pdf ·...

Current Monitoring for CML: Goals and

Principles Principles

Jorge Cortes, MDChief, CML & AML SectionDepartment of Leukemia

MD Anderson Cancer Center

Survival in Early Chronic Phase CML

MDACC 2009

Chromosome 9Chromosome 22

BCR

5’

1b

1a

a2

a3

5’

3’

e1

e1’e2’

b1

b5

m-bcr

M-bcr

The Philadelphia Chromosome

ABL5’

3’

a3

a11

b5

e19µµµµ -bcr

e1a2

b2a2

b3a2

e19a2

p190bcr-abl

p210bcr-abl

p230bcr-abl

The Significance of Philadelphia Chromosome and BCR-ABL in CML

Significance Implication

Pathophysiology Disease Pathophysiology Disease

Specificity Monitoring

Oncogene addiction Treatment

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108

1010

CMLCML

Evaluating Response in CML

3 log reduction Molecular response

CCR (CG)

MCRCytogenetic

responseCCR (FISH)

CHR Hematologic response

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104

CMLCML 3 log reduction

Limits of detection

4 log reduction

Molecular response (Q-PCR)

Evaluating Response in CMLN

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f le

uk

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ic c

ell

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1012

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3 log reduction

Imatinib

CCR (CG)

MCR

InterferonCCR (FISH)

CHR Hydroxyurea

Response is surrogate marker

11

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3 log reduction

Limits of detection

4 log reductionImatinibfor long term outcome

rb2JC2

rb2 Suggested to change imatinib to TKIs by one reviewer. (However, log reduction was defined by imatinib.) Please comment. rbloechlinger, 2/28/2011

JC2 This is a historical perspective and these levels were established with imatinib so I prefer to keep as is.jecortes, 2/28/2011

Definitions of Cytogenetic Response

Response Criteria

CHR

WBC <10 x 109/LPlatelets <450 x 109/L

PB myelo + metamyelo <5% No PB blasts + promyelo

PB basophils <20% No extramedullary No extramedullary

involvement

Cytogenetic* % Ph+ Metaphases

Complete 0Major

Partial 1-35

Minor 36-95*Based on standard karyotype, 20 metaphases (not FISH)

Molecular Response in CML

•Real time PCR = BCR-ABL/control x 100

•Major molecular response (MMR)

−BCR-ABL/control <0.1% (IS)

−3 log reduction (from standardized baseline)

−Using reduction from individual baseline

8

−Using reduction from individual baseline not validated

•Complete molecular response (CMR) = PCR negative, sensitivity 4- to 5-log

−CMR4, CMR4.5, CMR5

−BCR-ABL/control ≤0.0032% (IS)

−Undetectable

IRIS Study in Chronic Phase CML• 553 pts randomized to imatinib 400 mg/D; 8-yr

follow up

• Annual transformation rate to AP/BP (yrs 4-8): 0.9%, 0.5%, 0%, 0%, 0.4%

• Only 15 pts in CCyR (3%) progressed to AP/BP

• No pts in MMR at 12 mos progressed to AP/BP

• Outcome at 8 yrs Percent• Outcome at 8 yrs Percent

On study 55

CCyR 83

MMR 86

EFS 81

PFS 92

OS (CML deaths only) 85 (93)

Deininger et al; Blood 2009; 114: Abst# 1126

Monitoring Procedures in CML• CG: looks at all chromosomes; but:

tedious; needs metaphases; only 20 cells counted (95% CI CCyR 15%); painful BM

• FISH: faster; 200 cells; PB; but: false (+) up to 5-10%; no information on other

10

up to 5-10%; no information on other chromosomes

• PCR: most sensitive; PB; evaluable in CCyR; predicts for relapse; but: not standardized; no information on other chromosomes; variability up to 0.5 log; use 1 source (PB) and 1 reliable lab

IFNαααα in CMLSurvival by CG Response

PR

OP

OR

TIO

N A

LIV

E

0.6

0.7

0.8

0.9

1.078 %

39 %

MONTHS (LANDMARK AT 12 MONTHS)

PR

OP

OR

TIO

N A

LIV

E

0.0

0.1

0.2

0.3

0.4

0.5

0 24 48 72 96 120 144 168 192

Total Dead

140 38 CR

72 40 PR

110 86 Minor

180 138 Others

(P < 0.0001)

39 %

25 %

Kantarjian et al. Cancer 2003; 97: 1033

Ma

rro

w% Ph+

100

80

60

Peripheral Blood FISH: Excellent Correlation With Bone Marrow FISH

Le Gouill et al. J Clin Oncol. 2000;18:1533.

Peripheral blood

Ma

rro

w

40

20

020 40 60 80 100

% Ph+

r=0.97

0

Correlation Between iFISH and Cytogenetics in CML

ResponsePercentage FISH +

<1% 1-5% >5%

CCyR 83 13 4

PCyR 9 42 49

CCyR & MMR 92 7 2

Testoni et al, Blood 2009; 114: 4939-43; Testoni et al, ASH 2006, abst #4779

Can PCR Replace Cytogenetic Analysis?

PCyR?

Ross DM et al. Leukemia 2006; 20: 664-70

CCyR?

Survival for CML Clonal Evolution with Imatinib

Cortes et al. Blood 2003; 101: 3794

CG Abnormalities in Ph(-) Cells

•41 of 261 pts (16%) treated with imatinib

–+8 (n=8); -5/-7 (n=11); 20q- (n=4); other (n=18)

•Transient in 29/41 (71%)

•36/41 remain in CG response •36/41 remain in CG response

–Major 31, Minor 5

–1/41 developed AP CML

•3 developed MDS⇒⇒⇒⇒AML (-7 in 2, 5q- in 1)

–20/41 (49%) G≥3 myelosuppressionMedina et al. Cancer 2003; 98: 1905-11Kantarjian et al. Blood 2004; 104: 1979

CG Abnormalities in Ph-negative Metaphases with IM Frontline Therapy

Overall Survival Progression-Free Survival

• 21/258 (9%) patients developed CG abnormalities in Ph-metaphases 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]

Jabbour et al. Blood 2007; 110: 2991-5

Detection of Del Der (9) using the Vysis ES Probe

Prognostic Significance of Deletion of der(9) in CML Patients Treated with Imatinib

• Huntly et al1 (n=397)

– Deletion der(9) in 59 (15%)

– Inferior response rate to imatinib

– More rapid disease progression

– Trend for inferior survival

• Quintas-Cardama et al2 (n=352)• Quintas-Cardama et al (n=352)


– No impact on response, remission duration or survival by MVA

• Castagnetti et al3 (n=521)


– 12 month CCyR rates were 82%/85% and MMR 69%/65%, respectively (with/without del der(9))1Huntly et al. Blood 2003; 102: 2205-2212; 2Quintas-Cardama et al. Blood 2005; 105: 2281-6

3Castagneti et al. JCO 2010; 28; 2748-54

Spectral Karyotyping (SKY)

Evaluation of Molecular Response in CML

• Quantitative-RT-PCR (Q-RT-PCR) detects bcr-abl transcripts

% w

ith

ou

t p

rog

ressio

n

50

60

70

80

90

100

IRIS – 5-yr EFS by Molecular Response With Imatinib at 12 Months

CCyR with MMR

CCyR without MMR

No CCyR

% w

ith

ou

t p

rog

ressio

n

0

10

20

30

40

50

Months since randomization0 6 12 18 24 30 36 42 48 54 60

97% 89% 72%

Estimated rate at 60 months

p<0.001p=0.017

Baccarani et al. ASH 2006, abs 2138.Event = AP-BP on IM; death any cause on IM; loss of CHR or MCyR; or ↑ WBC.

rb6

rb6 Please add definition of EFS to slidesrbloechlinger, 2/28/2011

IRIS – 7-yr EFS by Molecular Response With Imatinib at 12 Months

% W

ithout E

vent

50

60

70

80

90

10092%91%

64%

53%

P = .25

BCR-ABL % (IS)

<=0.01%>0.1-1%>1-10%>10%

% W

ithout E

vent

0

10

20

30

40

50

Months Since Start of Treatment

0 12 24 36 48 60 72 84

53%

≤ 0.1% (n = 153)

>0.1-1% (n = 90)

>1-10% (n = 36)

>10% (n = 22)

(n=301)

≅≅≅≅ CCyR

Hughes T, et al. Blood 2010; 116: 3758-65Event = AP-BP on IM; death any cause on IM; loss of CHR or MCyR; or ↑ WBC.

% W

ithout E

vent

50

60

70

80

90

100

86%

95%

62%58%

P = .01

IRIS - EFS by Molecular Response With Imatinib at 18 Months

BCR-ABL % (IS)

<=0.01%>0.1-1%>1-10%>10%

% W

ithout E

vent

0

10

20

30

40

50

Months Since Start of Treatment

0 12 24 36 48 60 72 84

≤0.1% (n = 164)

>0.1-1% (n = 47)

>1-10% (n = 25)

>10% (n = 13)

(n=249)

≅≅≅≅ CCyR

Hughes T, et al. Blood 2010; 116: 3758-65Event = AP-BP on IM; death any cause on IM; loss of CHR or MCyR; or ↑ WBC.

rb7

rb8

rb7 Add definition of EFS. Original definition of IRIS does not include loss of CCyR.rbloechlinger, 2/28/2011

rb8 Loss of CCyR is now considered and important event, while it was not included in the original definition of EFS. When loss of CCyR isn included them MMR becomes important and signicrbloechlinger, 2/28/2011

7-Year Outcome by Molecular Response – All Patients

LandmarkPercentage

MMR No MMR

6 mo

EFS 85 84

TFS 96 93

OS 90 89OS 90 89

12 mo

EFS 91 79

TFS 99 90

OS 93 89

18 mo

EFS 95 75

TFS 99 90

OS 95 90

Hughes T, et al. Blood 2010; 116: 3758-65

7-Year Outcome by Molecular Response – Only Patients with CCyR

LandmarkPercentage

MMR No MMR

6 mo

EFS 85 93

TFS 96 98

OS 90 93OS 90 93

12 mo

EFS 91 92

TFS 99 96

OS 93 97

18 mo

EFS 95 86

TFS 99 96

OS 95 96


Time to Loss of CCyR by Molecular Response at 18-Months


60

80

100

60

80

100

Significance of CMR in CML After Imatinib Therapy

CMR (n=28)CMR (n=21)

18-month landmark

free s

urv

ival (%

)

free s

urv

ival (%

)

Overall 18-month Landmark

0

20

40

60

0 10 20 30 40 50

0

20

40

60

0 10 20 30 40 50

CMR = complete molecular response.

MMR = major molecular response

MMR, not CMR (n=48)

P=0.0052

Months after MMR

MMR, not CMR (n=29)

P=0.0080

Months after MMR

Rela

pse-f

ree s

urv

ival (%

)

Rela

pse-f

ree s

urv

ival (%

)

Press et al. Clin Cancer Res 2007; 13: 6136-43

Significance of Sustained CMR in CML• 261 pts treated with frontline imatinib • Sustained CMR in 32% [undetectable (sensitivity ≥4.5-log)

in ≥ 2 consecutive assays over ≥6 mo]• Median time to sustained CMR 30 mo (6-84 mo)

Event-Free Survival Transformation-Free Survival

Verma et al. Blood 2009; 114; Abst# 505

Imatinib Treatment DiscontinuationsThe 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–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-startMahon et al. Blood 2009; 114: Abst# 859

Patterns of Transcript Levels After Imatinib

10

1

0.1

100

AB

L/A

BL

rati

o (

%)

Cytogenetic relapse

In plateau

CCyR

12 18 24 30 36 6

0.01

0.001

0.0001

BC

R-A

BL

/AB

L r

ati

o (

%)

Months from start of imatinib

Continuing to decline

Marin et al. Leukemia 2005; 19: 507-12

•Plateau = log10 of most recent BCR–ABL/ABL ratio was no more than 0.25 'lower' than the log10 of the mean BCR–ABL/ABL ratios measured after 18 months from the start of imatinib

Increasing Transcript Levels in CML

40

50

60

70

80

90

No

. P

ati

en

ts“We conclude that a rise in BCR-ABL of more than 2-fold can be used as a

primary indicator to test patients for

0

10

20

30

40

No

. P

ati

en

ts

<0.1 >0.1 <0.1 >0.1

>2x increase Stable or decrease

Mutation No Mutation

Branford et al. Blood 2004; 104: 2926-32

primary indicator to test patients for BCR-ABL kinase domain mutations.”

Loss of CG CR by ⇑⇑⇑⇑ in Transcript Levels

4

6

8

10

12

14

16

18

No. patie

nts

CGCR lost

CGCR not lost

0

2

4

MMR No MMR MMR No MMR MMR No MMR

<1-log 1-2-log >2log

Log increase by lowest transcript level

No. Best Mol Resp No. lost CG CR (%) p

37 MMR 1 (3)0.0006

24 No MMR 9 (38)Cortes et al. Clin Cancer Res 2005; 11: 3425-32

Half-log Increase in Transcript Levels Predicts relapse in CML

Press et al, Clin Cancer Res 2007; 13: 6136-43

Receiver Operating Characteristic Analysis To Define The Optimal qPCR Trigger

Press et al. Blood 2009; 114: 2598-605

Significance of Rising MRD in CGCR on Imatinib

• 116 pts in durable CGCR on imatinib ≥18 mos had ↑↑↑↑QPCR ≥0.5 log

• 11/116 (9%) had CML progression

• 10/44 (23%) progression if : loss of MMR or not in MMR and ↑↑↑↑ QPCR ↑↑↑↑ > 1 log

• ↑↑↑↑•Status ↑↑↑↑QPCR No. CML progression

MMR Any 28 0

Loss of MMR 0.5-1

>1

12

36

0

6

Not in MMR <1

>1

32

8

1

4

Kantarjian et al. JCO 2009; 27: 3642-9

Criteria for Failure and Suboptimal Response to Imatinib

Time (mo)Response

Failure Suboptimal Optimal

3 No CHRNo CG

Response<65% Ph+

6No CHR

>95% Ph+≥35% Ph+ ≤35% Ph+Lack or loss of

molecular 6

>95% Ph+≥35% Ph+ ≤35% Ph+

12 ≥35% Ph+ 1-35% Ph+ 0% Ph+

18 ≥5% Ph+ No MMR MMR

Any

Loss of CHRLoss of CCgR

MutationCE

Loss of MMRMutation

Stable or improving

MMR

Baccarani et al. JCO 2009; 27: 6041-51

molecular response is not a criterion for

failure

rb10JC4

rb10 Suggest to indiecate MMR is part of the ELN Optimal Response Criteriarbloechlinger, 2/28/2011

JC4 That is not my side of the argument for this debate.jecortes, 2/28/2011

What is Not Failure to Therapy in CML

• FISH 1-10%

• No MMR at 12 months

• PCR still positive• PCR still positive

• Increasing transcript levels

• Chromosomal abnormalities in Ph-negative metaphases

The Simple Interpretation of Molecular Results

• If it is going down, it is good

• If it is stable, it is OK

• If it is going up, monitor more frequentlyfrequently

–Not a failure by itself

• First, optimize therapy; then:

–Consider low-risk strategies (eg, vaccines)

–Dasatinib, nilotinib?Whitehead AN & Ruyssell B. Principia Mathematica. Cambridge Uniuversity Press. 1910.

Reproducibility of CCyR and MMR Across CML Frontline Trial

Median (range) 67 (59-74) 27 (15-39)

Mean (95% CI) 67 (63-71) 28 (21-35)

Adapted from Baccarani et al. Blood 2010; abst #668

BCRBCR--ABLABLISIS after Conversionafter ConversionBCRBCR--ABL prior to ConversionABL prior to Conversion

1010

3 exchanges of patient samples May 05, April 06, Aug 06 3 exchanges of patient samples May 05, April 06, Aug 06

AB

L%

AB

L%

IS

IS

100100

Ref LabRef Lab

Lab 5 Lab 5

CF 1.25CF 1.25

CF 0.239CF 0.239

-- BCRBCR

-- ABLABL

Branford, 2006, Blood, 108, abstract 737Branford, 2006, Blood, 108, abstract 737

Ref Lab Lab 5

median 0.97%median 0.72% P=0.9

38 Patient Samples38 Patient Samples0.0010.001

0.10.1

1.01.0

0.010.01

BC

RB

CR

--AB

L%

AB

L%

Ref Lab Lab 5

median 0.78%median 3.10%P<0.0001

Important Considerations Regarding Molecular Monitoring in CML

• Maintain same source

• Maintain same lab

–IS to minimize this problem–IS to minimize this problem

• Consider variability of test

• Uniform reporting

• Needs: standardization, speed, access

So What Do We Get?

Response Translates into:

CCyRSignificantly improved survival

Improvement in EFS, Molecular Response is a

MMRImprovement in EFS, possible longer duration CCyR

CMRPossibility of consideringtreatment discontinuation (clinical trials only)

Molecular Response is a Measure of Success, Not a

Measure of Failure

Mechanisms of Resistance to Imatinib

• Bcr-Abl-Dependent

–Amplification/overexpression

–Mutations in Abl

–Remigration of Bcr-Abl to cytoplasm

• Bcr-Abl-Independent• Bcr-Abl-Independent

–Increased MDR expression

–Increased alpha-1 acid glycoprotein

–Overexpression of Src-related kinases

• Quiescent stem cells (Persistence)LeCoutre Blood 95: 1758, 2000.Weisberg Blood 95: 3498, 2000

Mahon Blood 96: 1070, 2000. JNCI 92:1641, 2000. Vigneri Nature Medicine 7: 228, 2001

Incidence of BCR-ABL Mutations after Imatinib Failure

Apperley J. Lancet Oncology 2007; 8: 1018-29

p = P-loop, b = imatinib binding, c = catalitic domain, a = activation loop

Technology Sensitivity Specificity Bias* Availability

Sequencing 10-15% +++ No +++

Subcloning and sequencing 5% +++ No ++

Denaturing high performance liquid chromatography (D-HPLC)

0.1-10% ++ No ++

Pyrosequencing 5% ++ No +

Methods for Detecting Mutations

Pyrosequencing 5% ++ No +

Double-gradient–denaturing-gradient gel electrophoresis (DG-DGGE)

5% ++ No +

Fluorescent PCR and PNA clamping

0.2% ++ Yes +

Allele specific oligonucleotide (ASO)-PCR

0.01% ++ Yes +

Sensitivity of Mutations to TKIBa/F3 cell proliferation IC50 (nM)

Imatinib Nilotinib Dasatinib

WT 260 13 0.8

M244V 2000 38 1.3

G250E 1350 48 1.8

Q252H 1325 70 3.4

Y253F 3475 125 1.4

Y253H >6400 450 1.3

E255K 5200 200 5.6

E255V >6400 430 11E255V >6400 430 11

V299L 540 ND 18

T315A 971 61 125

T315I >6400 >2000 >200

F317L 1050 50 7.4

F31TV 350 ND 53

E355G 2300 ND 1.8

F359V 1825 175 2.2

V379I 1630 51 0.8

H396P 850 41 0.6

H396R 1750 41 1.3

O’Hare et al. Blood 2007; 110: 2242-9Resistant / Moderately sensitive / Sensitive

CCyR by Mutations in CML Treated with 2nd

Generation TKI after IM Failure• 86/169 (51%) pts treated had mutation

• CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%)

• IC50 for dasatinib, nilotinib predictive for response in CP and AP

Chronic Phase Accelerated Phase

Jabbour et al, Blood 2009; 114: 2037-43

Inducible Mutations in Mutagenesis Studies with AMN and BMS

• Mutants induced by saturation, selection, or induced (ENU)

• Mutations: imatinib 20, nilotinib 10, dasatinib 9

DrugConcentration

DrugLow Intermediate

AMN L248V, G250E, F359C, L384M, L387F

Y253H, E255K/(V), T315I

BMS L248V, Q252H, E255K/V, V299L

T315I, F317C/L/V

Bradeen et al. Blood. 2006; 108: 2332-8; Ray et al. Blood. 2007; epub ahead of print; von Bubnoff et al. Blood. 2006; 108: 1328-33. Burgess et al. PNAS. 2005; 102: 3395-400.

Spectrum and frequency of BCR-ABL KD mutations recovered after TKI therapy

10

15

20

%

Imatinib

Dasatinib

Nilotinib

• T315I and F359V recovered after treatment with SKI-606

0

5

10

G250E Y253F/H E255G/K V299L F311I/L T315I F317L/V M351T E355G/A F359C/V H396P/R

BCR/ABL Mutation

Cortes et al. Blood 2007; 110: 4005-11

Outcome by Presence of Mutation Prior to Imatinib Exposure

Event-free Survival Overall Survival

• ASO-PCR for Q252H, Y253F, Y253H, E255K, E255V, T315I, M351T, and F359V in 66 pts

• Mutations in 14 (21%): 10/27 (37%) AP, 5/19 (26%), 0/20 CP

Willis et al. Blood 2005; 106: 2128-37

Mutation Detection by Outcome with Imatinib Therapy CML CP

• 462 pts treated on TOPS ⇒⇒⇒⇒ 280 mutation assay

• Mutation assay if: no MCyR by 6 m, no MMR at 12 m, loss of any response, progression to AP/BC, ⇑⇑⇑⇑ BCR-ABL

• 26 mutations identified in 20 pts (7%)

Response Months N mutations/tested (%)

No CHR 3 0/22 (0)

>95% Ph 6 0/15 (0)>95% Ph 6 0/15 (0)

No MCyR 12 6/25 (24)

MCyR, no CCyR 12 3/31 (10)

No MMR 18 5/101 (5)*

AP/BP Any 3/14 (21)

Loss CHR Any 7/17 (41)

Loss MCyR Any 4/11 (36)

Loss CCyR Any 1/8 (13)

Loss MMR Any 6/45 (13)

* Failed to achieve CCyR Branford et al. Blood 2010; Abst# 889

Singificance of KD Mutatons in Patients Responding to Imatinib

• 10 of 214 (5%) pts who achieved CCyR had mutation

– 4 before CCyR

• Median time from

PFS by Mutation at 2 Yrs

• Median time from mutation to loss CCyR 20.7 months

• Median time from detection of mutation to 2-fold ⇑⇑⇑⇑ PCR 12 mo

• KD mutation predictive of loss of CCyR

Khorashad et al. J Clin Oncol 2008; 26: 4806-13

Analysis of Mutations in CML• Over emphasized; results produce more false

therapeutic leads than benefits

• No role for mutation studies pre-Rx or in imatinib responding patients

• If CG or hematologic relapse, mutations studies may help

–T315I: no role for new TKIs; allo SCT or –T315I: no role for new TKIs; allo SCT or others (HU, ara-C, HHT, “T315I inhibitors”)

–Nilotinib IC50>150nM (e.g. Y253H, E255V, F359V) ⇒⇒⇒⇒ Dasatinib

–Dasatinib IC50>3nM (e.g. F317L, V299L) ⇒⇒⇒⇒Nilotinib

• But: ~50% have no mutations, and no difference or no information for most

Monitoring Recommendations for CML According to the ELN 2009

Objective Recommended frequency

Hematologic•Every 2 wk until CHR, then at least every 3

mo or as required

•At diagnosis, 3 mo, 6 mo and every 6 mo until confirmed CCyR, then every 12 mo if

Cytogeneticuntil confirmed CCyR, then every 12 mo if molecular monitoring not assured

•At failure or unexplained myelosuppression

Molecular•Every 3 mo until MMR confirmed, then every

6 mo

Mutations• In case of failure or suboptimal response, or

before change to 2nd TKI

Baccarani et al. JCO 2009; 27: 6041-51

Approaches to Monitoring in CML• The conservative approach

– CG every 6 mo until CCyR, then every 6-12 mo• The FISHer approach

– No CG– Use FISH to evaluate “molecular” response

• The molecular enthusiast approach– PCR only, every 3 months

•– PCR only, every 3 months

• The “I-don’t-care-about-any-such-studies” approach– CBC only

• The hybrid approach– Baseline CG (+FISH? +PCR?)– BM (CG) every 6-12 mo until CCyR, then every 1-2 yrs– FISH every 3mo until “negative”– PCR every 3 mo during 1st yr, then every 6 mo

• Mutations when clinical failure

Kantarjian et al. Blood 2008; 111: 1774-80

Not everything that counts can be counted, and not everything that can be

counted counts.counted counts.

Albert Einstein (1879-1955)

(Sign hanging in Einstein's office at

Princeton)

Questions?

[email protected]@mdanderson.org

713-794-5783

current monitoring for cml: goals and principles monitoring webinar with dr. jorge cortes.pdf ·...

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