Is the “wait and watch” philosophy still practical in the treatment of CLL even in younger patients ?

Federico Caligaris-CappioUniversity Scientific Institute San RaffaeleDept Oncology, Div Molecular OncologyMilano, Italy

The 1° World Congress on Controversies in Hematology (COHEM)

Rome, September 2010

Expected to say NO

Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.

Shanafelt, T. D. Hematology 2009;2009:421-429

Figure 1. Overall survival of CLL patients relative to age-matched controls

0% 20% 40% 60% 80% 100%

1995-

1990-94

1985-89

1980-84

1975-79

< 1975

Binet A Binet B Binet C

CLL: Proportion of patients diagnosed in early stage

EHFV, Barcelona

FCC, Inside Blood, 2009 Natural History

“..Catastrophes usually dependupon a combination of errors ”

…….As time goes by…….

“..Catastrophes usually dependupon a combination of errors ”

…….As time goes by…….

M.Twain: “Age is an issue of mind over matter. If you don’t mind, it doesn’t matter”

Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation statusP Grabowski et al. BLOOD, 2005, 105, 4807

Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutationsRN Damle et al. BLOOD, 2004, 103, 375

HydrogenHydrogen DeuteriumDeuterium

2H2O

B-CLL cellsB-CLL cells

Gas chromatography/Gas chromatography/Mass spectrometryMass spectrometry

In vivoIn vivo measurement of CLL cell kinetics measurement of CLL cell kinetics by labeling dividing cells with deuterium (by labeling dividing cells with deuterium (22H) H)

Newly synthesized DNANewly synthesized DNA

Results of previous B-CLL cell kinetic studies using Results of previous B-CLL cell kinetic studies using 22HH22O O

Messmer B. Messmer B. et alet al, JCI 2005, JCI 2005 Defoiche Defoiche J.J. et alet al, BJH 2008, BJH 2008 Van Gent R.Van Gent R. et alet al, Cancer Res., , Cancer Res., 20082008

CLL clones are definitely more “dynamic” than presumed

Increased proliferation entails increased genetic risk(TIME MATTERS)

WHO TO TREAT ? WHEN TO TREAT ?

PROGNOSTIC FACTORS

The question is whether we may determine if an individual young CLL patient at presentation, with early stage disease, will have stable progression-free disease and long overall survival or progress rapidly, develop complications and die

April 2002Male 29 yrs old, excellent health conditions, physically fit Incidental diagnosis of CLL with 50.000 WBC, lymphadenopathy

June 200285.000 WBC, lymphadenopathy, palpable tip of spleen, no B signs.BM: 65% lymphocytes No molecular nor cytogenetic nor sophisticated cytofluorograph analysis

BMT advised

Patient A.B.

April 2002Male 29 yrs old, excellent health conditions, physically fit Incidental diagnosis of CLL with 48.000 WBC, lymphadenopathy

June 200285.000 WBC, lymphadenopathy, palpable tip of spleen No molecular nor cytogenetic nor sophisticated cytofluorograph analysis

June 201089.000 WBC, lymphadenopathy, palpable tip of spleenExcellent health conditions, physically fit

Deletion 13q14, IGVH mutated, CD38 < 1%, ZAP70 neg

Patient A.B.

No Treatment

April 2005Female 44 yrs old with sporadic feverFather died in 1997 of CLL. Aunt (father’s sister) has stage 0 CLL Diagnosis of CLL with 32.000 WBC, hypogammaglobulinaemia, micro-lymphadenopathy.BM: 80% lymphocytesDeletion 13q14, IGVH 3-53 Unmutated CD38 18% (PB; 35% BM), ZAP70 30%

May 200682.000 WBC, lymphadenopathy slightly increased, palpable tip of spleen Weakness and unrelenting fever

January 2007CLL8 Protocol: FCR July 2010: Still Molecular Remission

Patient F.G.

Predicting outcome using Molecular – Biological Factors

• IGVH Mutation Status• CD38 • ZAP70• Recurrent Cytogenetic Abnormalities

Patient risk stratification in routine clinical practice

Work in Progress

Damle et al, 1999

IgVH Mutation status is aPrognostic Marker in CLL

Time from diagnosis

Hamblin et al, 1999

CD38 is a Prognostic Marker Independent of IgVH Mutation status

CD5

CD

38

Damle et al, 1999

Time from diagnosis

% s

urvi

ving

Which Cut-off Level for CD38 ?C

D38

+ CLL

Cel

ls (%

)90

80

70

60

50

40

30

20

10

0

100Damle et al, 1999 Ibrahim et al, 2001 Krober et al, 2002

CD19

CD

38

34.7%

CD38

Even

ts

0.4% 98.9%A B C

34.7%0.4% 98.9%D E F

Ghia P et al, Blood 2003

Cumulat

ive

Surv

ival

Time (months)

CD38 bimodal

CD38-

CD38+

1,2

1,0

0,8

0,6

0,4

0,2

0,0

- 0,20 100 200 300 400

1,2

1,0

0,8

0,6

0,4

0,2

0,0

0 100 200 300 400- 0,2

CD38< 30%

CD38≥30%

CD38+ and bimodal patientshave similar cumulative survival

Results of previous B-CLL cell kinetic studies using Results of previous B-CLL cell kinetic studies using 22HH22O O

Messmer B. Messmer B. et alet al, JCI 2005, JCI 2005

Frac

tion

of

Frac

tion

of 22 H

labe

led

cells

H la

bele

d ce

lls

Time (days)Time (days)

0 21 42 168

10

20

30

40

CD38CD38++

CD38CD38--

Intra-clonal kinetics heterogeneityIntra-clonal kinetics heterogeneity..Within each clone Within each clone CD38CD38++ cells cells proliferate faster than those proliferate faster than those CD38CD38-- . .

C. Calissano C. C. Calissano C. et alet al, Blood 2009, Blood 2009

Defoiche Defoiche J.J. et alet al, BJH 2008, BJH 2008 Van Gent R.Van Gent R. et alet al, Cancer Res., , Cancer Res., 20082008

Zap-70 expression identifies patients at risk of progression and shorter survival

Crespo et al, 2003

Rassenti, L. Z. et al. 2004

Zap-70 expression is a continuum

M M M M UM UM

13q- singlen=117

Survivalin %

Time in Months

11q-n=56

+12n=47

17p-n=23

0 36 72 108 144 1800

20

40

60

80

100

00

00

00

Genomic Aberrations and Survival in CLL

H.Dohner et al, NEJM,2001

A personal biased use of prognostic tests for young

early stage (Rai 0-1) asymptomatic CLL patients FISH testing (17p-, 11q-)IGVH Mutational StatusCD38ZAP70

All Positive17p- or 11q-IGVH UnmutatedCD38 PositiveZAP70 Positive

All NegativeAbsence of 17p- and 11q-IGVH MutatedCD38 NegativeZAP70 Negative

All PositiveHigh Risk

All NegativeLow Risk

W&WBe Ready to Treat

Variable Combinations17p- or 11q-IGVH UnmutatedCD38 PositiveZAP70 Positive

Variable Combinations(at least two markers)Intermediate Risk

Careful Follow-Up

The (wrong) concept of surrogate markers

The confusing need of cut-off

The prognostic significance of stereotyped receptors

The prognostic significance of microRNA signatures

Unclear Issues

The prognostic significance of MBL

Subsets of patients carrya similar “stereotyped” HCDR3

H

L

H

L

P. Ghia et al Blood 2005The case of IGHV3-21-expressing CLL

HeterogeneousHCDR3

StereotypedHCDR3

Clinical implications:Homologous HCDR3 correlate with outcome

Time (months)

Cumulat

ive

even

ts

IGHV3-21

Time (months)

Survival Functions

TIME

4003002001000-100

Cum

Sur

viva

l

1,2

1,0

,8

,6

,4

,2

0,0

-,2

IGHV

2

2-censored

1

1-censored

“QWL”

HeterogeneousHCDR3

StereotypedHCDR3

Cumulat

ive

even

ts

Ghia et al, Blood 2005Stamatopoulos et al, Blood 2007

CD5

CD19

MBLMonoclonal B-cellLymphocytosis

Chronic Lymph Leukemia

CLL-like MBL are frequentRawstrom et al 2002, 2008, Ghia et al 2004,Dagklis et al, 2009

MBL is not relevant unless detected in first-degree relatives of CLL pts from high-risk families (17-foldhigher in young adults (16-40 yrs) when MBL is virtually non-existing in the general populationRawstron, Blood 2002; de Tute, Leukemia 2006, Marti Cytometry 2003

MBL virtually always precede thedevelopment of overt CLL (1.1% yr)Landgren et al 2009