CLL in M.B. van t Veer

Transcription

1 CLL in 2009 M.B. van t Veer

2 Questions in CLL: what is CLL? when to treat? how to treat CLL?

3 What is CLL?

4 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 years of age chromosomal abnormalities as in CLL skewed repertoire of IGVH genes as in CLL progression to CLL 1.1% per year

5 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

6 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.

7 When to treat CLL?

8 Recommandations regarding indications for treatment in CLL treat with Rai stage 0 treat with Binet stage A treat with Binet stage B or Rai stage I or II treat with Binet stage C or Rai stage III or IV treatment of active/progressive disease treatment without active/progressive disease General practice No No possible Yes Yes No Clinical trial RQ RQ possible Yes Yes RQ RQ: research question Hallek M. et al. Blood 2008

9 NCI criteria for active CLL ( Hallek et al ) Criteria 1. 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 o F for >2 weeks without evidence of infection d. Night sweats without evidence of infection 2 Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia and/or t hrombocytopenia 3. Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid therapy 4. Massive (ie, >6 cm below the left costal margin) or progressive splenomegaly 5. Massive nodes or clusters (ie, >10 cm in longest diameter) or p rogressive lymphadenopathy 6. progressive lymphocytosis with with an increase of >50% over a 2 -month period, or an anticipated doubling time of less than 6 months 7. Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria is not sufficient for protocol therapy

10 How to treat CLL? What is the standard in first line treatment?

11 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

12 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)

13 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

14 CLL Binet stage A: chlorambucil vs. no treatment. (overall survival) Dighiero G et al. N Engl J Med (1998)

15 CLL: chlorambucil vs. F vs. FC LRF CLL4 trial the MRC trial N CR OR PFS OS at 5 years chlorambucil 387 7% 72% 10% no F % 80% 10% difference at 5 years FC % 94% 36% Catovsky et al. Lancet 2007

16 CLL8: FC vs R-FC in first line N ORR CR PFS2year OS2year FC % 27% R-FC % 52% 76,6 91 WHO BENEFITS MOST: Binet A and B, good performance, normal renal function Hallek et al. (for GCLLSG); ASH 2008

17 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 Keating et al. (JCO 2005) 78 CD19/CD 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

18 CLL: first line treatment in patients with unfavourable prognosis: HOVON 68 - High risk CLL - Binet A *, B*, C - * Indication for treatment R A N D O M I S E D FC x 6 FC + Alemtuzumab x 6 Evaluation after 3 cycles SD/PD : off study

19 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

20 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

21 CLL: alemtuzumab (CD52) in p53 defect patients in chemo- (fludara-) resistant patients

22 CLL: p53 and ATM in apoptosis

23 CLL and allo-psct: HOVON 88

24 CLL and allo-psct: HOVON 88

25 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: Van Besien K et al.

26 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)