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CLL in 2009
M.B. van ‘t Veer
Questions in CLL:
•
what is CLL ?
•
when to treat ?
•
how to treat CLL ?
What is CLL ?
CLL: WHO 2008
• > 5 x 10e9/l cells with CLL phenotype in blood
• Monoclonal B cell lymphocytosis (MBL)
– if < 5 x 10e9/l cells with CLL phenotype
characteristics MBL:
–
–
–
–
5,1 % in cases 62 –80 years of age
chromosomal abnormalities as in CLL
skewed repertoire of IGVH genes as in CLL
progression to CLL 1.1% per year
CLL: characteristics
• morphology
– small mature lymphocyte
• immunophenotype
– CD19+, CD20+, CD23+, CD5+, sIG(+)
• antigen experienced B cell
– CD5+, CD40+, CD38+, CD25+, gene expression profile
• no underlying single chromosomal abnormality
• turnover rate: 0.1% - 1% replaced each day
CLL: prognostic factors
• clinical stage
– Rai, Binet
• cytogenetics
– 13q-, tris 12, 11q-, 17p-, translocations
• IGVH mutation status
– Zap-70
– LPL (lipoproteine lipase)
• others
– lymphocyte doubling time, CD38, _2 microglobulin, etc.
When to treat CLL ?
Recommandations regarding indications for
treatment in CLL
General practice
Clinical trial
treat with Rai stage 0
No
RQ
treat with Binet stage A
No
RQ
treat with Binet stage B or Rai
stage I or II
possible
possible
treat with Binet stage C or Rai
stage III or IV
Yes
Yes
treatment of active/progressive
disease
Yes
Yes
treatment without
active/progressive disease
No
RQ
Hallek M. et al. Blood 2008
RQ: research question
NCI criteria for active CLL ( Hallek et al . 2008 )
1.
2
3.
4.
5.
6.
7.
Criteria
A minimum of any of the following disease -related symptoms must be present:
a. Weight loss >10% within the previous 6 months
b. Extreme fatigue (ie, ECOG PS2 or worse: cannot work or unable to p erform
usual activities)
c. Fevers of greater than 100,5 oF for >2 weeks without evidence of infection
d. Night sweats without evidence of infection
Evidence of progressive marrow failure as manifested by the development of , or
worsening of anemia and/or t hrombocytopenia
Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid
therapy
Massive (ie, >6 cm below the left costal margin) or progressive splenomegaly
Massive nodes or clusters (ie, >10 cm in longest diameter) or p rogressive
lymphadenopathy
progressive lymphocytosis with with an increase of >50% over a 2 -month period, or
an anticipated doubling time of less than 6 months
Marked hypogammaglobulinemia or the development of a monoclonal protein in the
absence of any of the above criteria is not sufficient for protocol therapy
How to treat CLL ?
What is the standard in first line
treatment ?
CLL: questions about treatment ?
• what are the objectives for treatment ?
– relief of complaints
– MRD
– cure
• should treatment be risk-adapted ?
– yes: but which factors ?
– no: use the less toxic therapy
Factors to be used in risk adapted
treatment
• performance state (comorbidity > age)
• clinical history (lymphocyte doubling time ?)
• biological prognostic factors (only in studies)
• 17p- (p53) deletion and progression: consider
aggressive therapy (alemtuzumab , allo PSCT)
CLL: therapeutic compounds
•
•
•
•
•
•
•
•
•
•
•
chlorambucil (Leukeran)
CVP, CHOP, CAP
fludarabine (F)
FC
rituximab + FC
alemtuzumab + FC
antibody maintenance therapy
radio-immunotherapy
gene therapy (antisense bcl-2)
new agents (flavoperidol, bendamustine, CD40)
allo PSCT
CLL Binet stage A: chlorambucil vs. no
treatment. (overall survival)
Dighiero G et al. N Engl J Med (1998)
CLL: chlorambucil vs. F vs. FC
the MRC trial
LRF CLL4 trial
chlorambucil
N
CR
OR
PFS
at 5 years
387
7%
72%
10%
F
194
15%
80%
10%
FC
196
38%
94%
36%
OS
no
difference
at 5 years
Catovsky et al. Lancet 2007
CLL8: FC vs R-FC in first line
N
ORR
CR
PFS2year
OS2year
FC
371
88%
27%
62
88
R-FC
390
95%
52%
76,6
91
WHO BENEFITS MOST: Binet A and B, good performance, normal renal function
Hallek et al. (for GCLLSG); ASH 2008
MRD and survival in first line chemo
therapy
Study
CR and
MRD-
Method
PFS: gain in
MRD- vs MRD+
CR
Robertson et al.(Blood
1992)
81%
CD19/CD5
> +21
78
CD19/CD15
+9
Del Poeta et al.
(Cancer 2005)
93%
3 colour
+6
Wendtner et al.
(Leukemia 2004)
83%
ASO-PCR
>+?
Milligan et al. (Blood
2005)
80%
IgH PCR
> -5
Maloum et al.
(Haematologica 2006)
62%
4 colour
>9
Keating et al. (JCO
2005)
CLL: first line treatment in patients with
unfavourable prognosis:
- High risk CLL
- Binet A *, B* , C
- * Indication for
treatment
R
A
N
D
O
M
I
S
E
D
HOVON 68
FC x 6
FC +
Alemtuzumab
x6
Evaluation after 3 cycles
SD/PD : off study
CLL: first line treatment in patients
not suitable for HOVON 68
• HOVON: chlorambucil
• vademecum 2008: chlorambucil ??
• proposal:
– younger: (R?-)FC
– elderly (frail): chlorambucil, (CVP), F
CLL: subsequent lines
• consider:
– inclusion in studies
– Alemtuzumab (+ FC) in patients with
• del 17p and/or p53 mutations
• F resistance
– allo PSCT
– repeat same therapy after long periods without treatment (> 18
months ?)
– in case of offert AIHA or AITP and if Fludarabine is indicated:
use (R) FC
CLL: alemtuzumab (CD52)
• in p53 defect patients
• in chemo- (fludara-) resistant patients
CLL: p53 and ATM in apoptosis
CLL and allo-PSCT: HOVON 88
CLL and allo-PSCT: HOVON 88
allo PSCT in CLL: rationale
•
•
TRM 25-50%
response rate 80%
•
•
•
survival plateau of 40-60%
relapse rate 10-25%
fraction of patients is cured? graft-vs-CLL effect?
Leukemia 2001; 15: 1317-1325
Van Besien K et al.
CLL: conclusions
•
•
•
•
heterogeneous with respect to biological features
several of these features are prognostic
no single underlying chromosomal abnormality
no cure (with conventional therapy)
For this reasons:
• risk adapted treatment (if possible in studies)
• consider allogeneic transplantation not too late in high
risk patients (del p53, chemo resistance)