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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)