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
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