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Chronische lymphatische Leukämie – Was ist neu?. Michael Hallek www.dcllsg.de. CLL: Stadium bestimmt Behandlung. CLL in frühen Stadien. CLL1: DESIGN AND STUDY POPULATION (n = 630). Binet stage A 877 pts. LDT <12/>12 months BM diffuse/non diffuse. Risk Stratification 804 pts.

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cll1 design and study population n 630
CLL1: DESIGN AND STUDY POPULATION (n = 630)

Binet stage A

877 pts

LDT <12/>12 months

BM diffuse/non diffuse

Risk Stratification

804 pts

TK ≤/> 7 U/L

ß2-MG ≤/> 3.5 mg/L

Inclusion/Exclusion ok

728 pts

LOW RISK

535 pts

HIGH RISK W&W

95 pts

n = 630

R

HR Fludarabine

98 pts

slide5

PFS AND OS RELATED TO RISK STRATIFICATION

LR = 522; Events = 262

HR W&W = 94; Events = 75

LR = 527; Events = 42

HR W&W = 93; Events = 19

p<0.001

p<0.001

major factors predicting an unfavorable course in binet stage a rai stage 0 cll
Major factors predicting an unfavorable course in Binet stage A/Rai stage 0 CLL
  • Chromosomal aberrations 17p- and 11q-
  • Elevated serum thymidine kinase (> 10 U/L)
  • Lymphocyte doubling time < 12 months
  • Unmutated IgVH gene
  • Expression of cytoplasmic ZAP70
  • Elevated surface expression of CD38?
cll7 protocol of the gcllsg fcllsg patients at binet stage a or b without symptoms
CLL7 protocol of the GCLLSG/FCLLSGPatients at Binet stage A or B without symptoms

Aim and Rationale: Complete (MRD-) eradication of early high risk disease

  • Assessment of 4 prognostic factors:
  • 11q- or 17p- deletion
  • Unmutated IgVH-Status
  • Serum thymidine kinase > 10 U/L
  • Lymphocyte doubling time < 12 months

Low risk:

< 2 factors positive

watch and wait

2/3 of patients

FCR

High risk: 2 or more factors positive

watch and wait

1/3 of patients

slide12

CLL5 protocol for elderly patients with advanced CLL

CLL,> 65 years, untreated, Binet stage C or symptomatic A/B

6 x Fludarabine phosphate

F 25 mg/m², Days 1–5q 28 days

Chlorambucil

(up to a maximum of 12 months)

Clb0.4 mg/kg body weight

increasing 0.1 mg up to 0.8 mg/kg body weight

q 15 days

cll5 protocol overall survival os
CLL5 protocol Overall Survival (OS)

p = 0.15

Median OS: F 45.8 months; Clb 63.6 months

cll5 protocol cause of death
CLL5 protocolCauseofdeath

Clb arm: 32 patients died

F arm: 42 patients died

first line r fc improved os following cr

p=0.16

p=0.10

p<0.01

p=0.12

First-line R-FC: improved OSfollowing CR

1.0

0.8

0.6

Probability

0.4

0.2

0

0

12

24

36

48

60

72

84

96

108

Time (months)

nPR = nodular PRPR-i = met all criteria for CR except for incomplete recovery of blood countsPR-d = residual disease in blood, nodes, spleen, marrow or other sites

Tam CS, et al. Blood 2008;112:975–80

f p vs f m c vs r fc improved survival with rituximab historical comparison

p<0.001

p=0.37

F±P vs F±M/C vs R-FC: improved survival with rituximab (historical comparison)

1.0

0.8

0.6

Probability

0.4

0.2

0

0

12

24

36

48

60

72

84

96

108

Time (months)

Tam CS, et al. Blood 2008;112:975–980

cll8 first line treatment of cll
CLL8: first-line treatment of CLL

6 x FCR

Final staging and follow-up

817 untreated patients with Binet B/C CLL randomised

6 x FC

Final staging and follow-up

  • In January 2008, the DSMB concluded that the study had reached the primary endpoint (PFS, difference of at least 35% at 2 yrs)
  • FCR is the superior study arm
slide19

Protocol amendment 1

Second to fourth-line therapy

First-line therapy

81 patients

119 patients

6 cycles BR

6 cycles BR

Bendamustine 70mg/m2 day 1-2 q4wks, cycle 1-6

Rituximab 375 mg/m2 day 0, cycle 1 500 mg/m2 cycle 2-6

Bendamustine 90mg/m2 day 1-2 q4wks, cycle 1-6

Rituximab 375 mg/m2 day 0, cycle 1 500 mg/m2 cycle 2-6

CLL2M

study design II

closed

closed

slide22

CLL 10 protocol of GCLLSG

Fludarabin

Cyclophosphamid

Rituximab

(FCR)

Fludarabine 25 mg/m² i.v., days 1-3

Cyclophosphamide 250 mg/m², days 1-3,

Rituximab: 375 mg/ m2 i.v. day 0, cycle 1

Rituximab: 500 mg/m² i.v. day 1, cycle 2-6

R

Bendamustin

Rituximab

(BR)

Bendamustine 90mg/m² day 1-2

Rituximab 375 mg/m² day 0, cycyle 1

Rituximab 500 mg/m² day 1, cycyle 2-6

Similar efficacy of BR in comparison to FCR?

Lower toxicity rate of BR?

slide23

3rd generation of trials of the GCLLSG:

Risk, stage and fitness adapted

Inactive Binet A

Active disease + all Binet C, not del(17p)

CLL12

CLL10

CLL11

Which is the best score to define high risk?

Go Go

Slow go

no

yes

W&W

W&W

treat

BR

FCR

CLB

CLB + R

Disease (MRD) eradication? Longer survival?

Symptom control?

longer disease-free survival?