Chronic lymphocytic Leukemia Georg Hopfinger 3. Med.Abt and LBI for Leukemiaresearch and Haematology Hanusch Krankenhaus,Vienna, Austria georg.hopfinger@wgkk.at
CLL Diagnosis and Staging Risk Profile Assessment Choice of Therapy
Diagnosis is easy Lymphocytosis > 5000/ µl Cytology Immunology FISH
Staging according to Binet Lnd Hb Plt Spleen Liver A < 2 >10 > 100 B > 2 >10 > 100 C - < 10 < 100
Prognostic Factors Clinical Stage RAI or Binet Lymphocyte doubling time < 1 year Cytogenetics /molecularbiology 11q- or 17p- Deletion Unmutated IgV H -Status Labor/ Immunphenotype beta-2 Mikroglobulin Serum Thymidine Kinase CD 23 CD 38 ZAP 70
Clinical and molecular Parameters Questions : 1. Are they available? 2. Do they impact on therapy? 3. Predictive for Progression? 4. Predictive for Survival?
Survival according to Binet Stadium Probability of survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Binet stage A Binet stage B Binet stage C 0 20 40 60 80 100 120 140 160 Time (Months)
Survival according to lymphocyte doubling time 1.0 Probability 0.8 0.6 0.4 LDT > 12 months LDT < 12 months 0.2 0.0 p<0.00001 AD < 12 months 0 12 24 36 48 60 72 84 96 108 120 132 144 Time (months) Mauro F, et al. Blood 1999;94:448 54.
Survival according to FISH and IGV H Mutation Status Genomic aberrations (n=325) 1 IgV H mutation status (n=211) 2,3 100 13q del only 100 Survival (%) 75 50 11q del 12q trisomy Survival (%) 75 50 Mutated 25 0 17p del Normal 0 24 48 72 96 120 144 168 25 0 P < 0.0001 Unmutated 0 24 48 72 96 120 144 168 192 216 Time (months) Time (months) 1. Dohner H, et al. N Engl J Med 2000;343:1910 16. 2. Rai K, et al. Hematology 2001:140 56. 3. Krober A, et al. Blood 2002;100:1410 16.
ZAP-70 Expression ZAP-70 expression and IgV H mutation status ZAP-70 expression and survival probability ZAP-70-positive cells (%) 80 60 40 20 IgV H Mutated Unmutated 0 ZAP-70-positive cells (%) <95% 95 98% >98% Probability of survival (%) 100 80 60 40 20 < 20% ZAP -70-positive cells 20% ZAP -70-positive cells p=0.01 0 0 4 8 12 16 20 24 28 32 120 IgV H Homology Year after diagnosis Crespo M, et al. N Engl J Med 2003;348:1764 75.
PFS for del(17p) and del(11q) Grever, M. R. et al. J Clin Oncol; 25:799-804 2007
Therapy General considerations When? No: Asymptomatic Binet A ( only trials) Yes:Symptomatic Binet A &B, Binet C How? Performance Status? Aim? Cytogenetics?
Overall Survival Binet A chlorambucil vs no treatment Dighiero G et al. N Engl J Med 1998;338:1506-1514
Mono Chemotherapy
Fludarabin 1st line n response(%) OS Rai FD vs CLB 509 63 vs 37 66 vs 56 NEJM 2000 (p=0.0001) French Cooperative FD vs CAP 100 71 vs 60 24 vs 24.5 Group Lancet 1996 Leporrier FD vs CHOP 938 71 vs 71 vs 58 69 vs 67 vs Blood 2001 CAP (p=0.0001) 70 Mo
Combination Chemotherapy
F vs FC Concerning CR % and Overall -Response % Fludarabin Fludarabin PFS Cyclophosphamide German trial 7/ 83 24 / 94 20 vs 48 Mo Eichhorst, Blood 2006 Uk trial 15/ 80 38 / 94 10 %vs 36% at 5 Yrs Catovsky,Lancet 2007 US trial 4,6/59 23.4/ 74 19.2 vs 31.6 Mo Flinn, JCO 2007
F vs FC PFS Eichhorst Blood 2006 Flinn,JCO 2007
Einfluss von 17p - nach F/FC Stilgenbauer ASH 2005
How can we further improve?
Monoclonal Antibodies in CLL HLA-DR CD52 slg CD20 CD23 MoAbs: Lymphocyte Anti CD 20 Rituximab Anti CD 52 Alemtuzumab Anti CD 23 Lumiliximab Adapted from Press O, et al. Cancer J Sci Am. 1998:4(suppl 2):s19 s26.
Rituximab monotherapy in CLL
Rituximab in relapsed CLL Huhn, D. et al. Blood 2001;98:1326-1331
Lower ORR in CLL Patienten 100 80 P=0.01 Possible causes: ORR (%) 60 40 60 lower CD20 Expression lower Rituximab Serum levels 20 13 higher Lymphocyte counts 0 FL SLL (CLL-type) Patients McLaughlin et al. J Clin Oncol. 1998;16:2825.
Dose Escalation 50 PatientS, CLL (with prior therapy) + other Rai III-IV Rai I-II with B Symptoms Dose 1 Dose 2-4 Kohorts n (mg/m2) (mg/m2) weekly A 19 375 500 B 4 375 650 C 3 375 825 D 4 375 1000 E 5 375 1500 F 12 375 2250 O Brien et al. J Clin Oncol. 2001;19:2165.
Dose Escalation ORR CLL Patients 100 Response Rate (%) 80 60 40 20 36 21 43 75 0 All CLL Patients (n=39)* 500-825 1000-1500 2250 (n=24)* (n=7)* (n=9)* * Evaluable patients. O Brien et al. J Clin Oncol. 2001;19:2165.
Rituximab + Chemo in relapsed /refractory CLL
FCR in relapsed CLL ORR: 73% CR: 25% PR (npr): 32% (16%) Molecular CR in 32% of CR Patients Fludarabin sensitive (n=108) Fludarabin resistant (n=37) ORR 76 59 CR 31 5 npr 17 11 PR 28 43 Wierda et al., J Clin Oncol 2005;23:4070 8
FCR in relapsed CLL : TTP and OS 1.0 0.8 No. of patients OS 177 80 Died TTP 129 60 Relapsed Probability 0.6 0.4 0.2 Median OS 39 months Median TTP 28 months OS TTP 0.0 0 6 12 18 24 30 36 42 48 54 Time (months) Wierda W, et al. J Clin Oncol 2005;23:4070 8
Rituximab in CLL first line
FR versus F in first -line CLL restrospective Comparison of 2 trials FR (CALGB 9712) vs F (CALGB 9011) F FR Patients (CALGB (CALGB 9011) 9712) N M Age (years) Rai III/IV (%) ECOG PS ORR (%) CR (%) 178 64 43 0 2 63 20 104 64 43 0 3 84 38 p= 0.003 p= 0.02 Byrd J, et al. Blood 2005;105:49 53.
FR vs F (retrospective) in first -line CLL PFS OS 1.0 1.0 Probability 0.8 0.6 0.4 FR Probability 0.8 0.6 0.4 FR 0.2 0 p<0.0001 0 20 40 60 80 100 120 140 Time (months) F 0.2 0 p=0.003 0 20 40 60 80 100 120 140 Time (months) F Byrd J, et al. Blood 2005;105:49 53.
FC-R first line in CLL 300 Patients 6 cycles R -FC every 4 weeks Keating M, et al. J Clin Oncol 2005;23:4079 88 Response CR npr PR No response Early death 6-Year OS: 77% 6-Year FFS: 51% Patients (n) 217 31 37 13 2 % 72 10 13 4 1 95% Tam C, et al. Blood 2008;15:112:975-980
Overall survival and time to progression by treatment response Tam, C. S. et al. Blood 2008;112:975-980
OS: historical Comparison 1.0 0.8 R-FC 0.6 FC/FM Proportion 0.4 0.2 F 0 Patients 190 140 300 Died 150 81 68 Treatment Fludarabine FC/FM R-FC 0 12 24 36 48 60 72 84 96 Months Tam C, et al. Blood 2008;15:112:975-980
CLL-8: R-FC vs FC in first line CLL untreated B -CLL Binet B with need for treatment or Binet C ECOG 0 1 N = 817 R A N D O M I S E R-FC q4wk 3 FC q4wk 3 R E S T A G E R-FC q4wk 3 CR, PR FC q4wk 3 MabThera Cycle 1: 375 mg/m 2 Cycle 2 6: 500 mg/m 2 Fludarabin 25 mg/m 2 iv, day 1 3 Cyclophosphamid 250 mg/m 2 iv, day 1 3 SD, PD off study
CLL-8: R-FC vs FC in first line CLL untreated B -CLL Binet B with need for treatment or Binet C ECOG 0 1 N = 817 R A N D O M I S E R-FC q4wk 3 FC q4wk 3 R E S T A G E R-FC q4wk 3 CR, PR FC q4wk 3 MabThera Cycle 1: 375 mg/m 2 Cycle 2 6: 500 mg/m 2 Fludarabin 25 Primary mg/m 2 iv, endpoint day 1 3 reached: > 35% SD, PD off study Cyclophosphamid PSF Benefit at two years! Data will be presented 250 mg/m 2 iv, at day ASH 1 3 2008,San Francisco EMEA accreditation pending
Future perspectives
Current Concepts of the DCLLSG CLL Binet A Asymptomatic CLL Binet C Symtomatic A and B CLL 7 CLL 2O CLL 10 17pwww.dcllsg.de
CLL7 Trial of the DCLLSG and French CLL Group Patients with Binet Stage A Aim and Rationale: complete eradication in high-risk patients Determination of risk factors: 1. 11q- or 17p- Deletion 2. Unmutated IgV H -Status 3. Serum TK > 10 U/L 4. LDT < 12 Mo Low risk: <2 Factors High risk:> 2 Faktors Observation FC+Rituximab Observation