John Gribben Professor of Experimental Cancer Medicine, Director of the Experimental Cancer Medicine Centre and Director of Stem Cell Transplantation at St Bartholomew’s Hospital, Queen Mary’s School of Medicine, University of London, UK Former Research Fellow in Haematology at University College London, UK Former Associate Professor of Medicine at Harvard Medical School, Boston, Massachusetts, USA Former Attending Physician at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts, USA Author of more than 300 manuscripts and book chapters Founding member of the CLL Research Consortium Associate Editor of Blood St Bartholomew’s Hospital
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John GribbenProfessor of Experimental Cancer Medicine, Director of the Experimental Cancer Medicine Centre and Director of Stem Cell Transplantation at St Bartholomew’s
Hospital, Queen Mary’s School of Medicine, University of London, UK
Former Research Fellow in Haematology at University College London, UK
Former Associate Professor of Medicine at Harvard Medical School, Boston, Massachusetts, USA
Former Attending Physician at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts, USA
Author of more than 300 manuscriptsand book chapters
Founding member of the CLL Research Consortium
Associate Editor of Blood St Bartholomew’s Hospital
– infectious prophylaxis during treatment and 2 months after
Patient characteristics
– mean age: 59 years (36–81 years)
– Rai stage III/IV: 49%
– median number of prior treatments: 2 (1–10)
– 46% of patients completed 6 cycles; 37% 3 cycles
Wierda W, et al. J Clin Oncol 2005;23:4070–8
R-FC for previously treated CLL:median survival over 3 years
Outcome nPatients at t=0
(n)
Died 80 177
Relapsed 60 129
Months
Overall survival (OS)
Time to progression (TTP)
Median OS: 42 months
Median TTP: 28 months
0 6 12 18 24 30 36 42 48 54
Pro
bab
ility
1.0
0.8
0.6
0.4
0.2
0
Rituximab doseCycle 1: 375mg/m2
Cycles 2–6: 500mg/m2
R-FC for previously treated CLL:TTP by response status
Pro
bab
ility
0 6 12 18 24 30 36 42 48 54
1.0
0.8
0.6
0.4
0.2
0
Months
n ResponseMedian
(months)
45 CR 39
28 Nodular CR 33
56 PR 15
Wierda W, et al. J Clin Oncol 2005;23:4070–8
NR = no response; ED = early death
n ResponseMedian
(months)
51 CR 45+
28 Nodular CR 30+
56 PR 39
42 NR 11
6 ED 2
R-FC for previously treated CLL:OS by response status
Wierda W, et al. J Clin Oncol 2005;23:4070–8
Pro
bab
ility
0 6 12 18 24 30 36 42 48 54
1.0
0.8
0.6
0.4
0.2
0
Months
R-FC is well tolerated in patients with previously treated CLL
Tolerability – no serious infusion-related adverse events– grade 3/4 neutropenia 62% of courses – grade 3/4 thrombocytopenia 17% of courses– major infection 5% of courses
Wierda W, et al. J Clin Oncol 2005;23:4070–8
R-FC in relapsed/refractory CLL: response by treatment regimen
Patients (%)
F ± P*(n=251)
FC*(n=111)
R-FC(n=143)
CR 13 12 28
Nodular PR 25 16 14
PR 21 39 30
NR 28 24 24
Early death 11 7 4
Wierda W, et al. Cancer 2006;106:337–45
*Historical controlsP = prednisone
59 67 72
R-FC in relapsed/refractory CLL: OS by treatment regimen
Wierda W, et al. Cancer 2006;106:337–45
1.0
0.8
0.6
0.4
0.2
00 24 48 72 96 120 144 168 192 216
Pro
po
rtio
n s
urv
ivin
g
Patients Died
Median survival (months) Protocol p value
251 241 20 F ± P
111 87 31 FC
143 669 49 R-FC
<0.01
0.05
Months
Increasing response rates in relapsed/refractory CLL
ORR (%) CR (%)
Chlorambucil/CAP 22–35 0–6
Fludarabine 32–59 3–37
FC 40–80 3–15
R-FC 73 25
Gribben J. Hematology (ASH Education Book) 2005;292–8O’Brien S, et al. J Clin Oncol 2001;19:1414–20
*375mg/m² dose adjustment for cycle 1 onlyA = alemtuzumab
1 2 3 4 5
Wierda WG, et al. Blood 2006;108:31 (Abstract 2839)
R-FCA in relapsed CLL: response by previous treatment
No. of patients (n=78)
CR after R-FCA (%)
ORR afterR-FCA (%)
FC
First line
Salvage
3
7
0
14
100
43
R-FC
First line
Salvage
20
25
30
16
65
48
SCT 4 25 75
Wierda W, et al. Blood 2006;108:14a (Abstract 31)
R-FCA in relapsed CLL: progression-free survival
Pro
port
ion
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36Months
27 months10 months
Patients Relapsed Response
19 5 CR
32 14 PRp<0.001
CR
PR
Wierda W, et al. Blood 2006;108:14a (Abstract 31)
R-FCA in relapsed CLL: OSP
rop
ort
ion
1.0
0.8
0.6
0.4
0.2
0 0 6 12 18 24 30 36 42Months
Patients Died Response19 2 CR32 21 PR27 22 SD/PD
0.007
0.008
p value
Wierda W, et al. Blood 2006;108:14a (Abstract 31)
R-PC in relapsed/refractory CLL
Regimen (all drugs administered on day 1 of a 3-week cycle for a total of 6 cycles)– R 375mg/m2 – P 4mg/m2
– C 600mg/m2
32 patients with relapsed/refractory CLL– eight patients fludarabine-refractory
ORR 75%, CRR 25%– six of eight fludarabine-refractory patients responded
with one CR
Of three patients with 17p deletion, two achieved a CR and one a PR
Lamanna N, et al. J Clin Oncol 2006;24:1575–81 R-PC = rituximab, pentostatin, cyclophosphamide
Case study 56-year-old woman presents in 1997 with
– cervical lymphadenopathy
– no B symptoms
– WBC WNL CT scan
– cervical and inguinal lymphadenopathy
– no splenomegaly LN biopsy: small lymphocytic lymphoma BM biopsy: diffuse infiltrate with CD19+CD5+CD23+
small B cells FISH of BM sample reveals del 13qWBC = white blood cell; WNL = within normal limits; CT = computed tomographyLN = lymph node; BM = bone marrow; FISH = fluorescence in-situ hybridisation
Case study (cont’d) Watch and wait approach explained to patient
Over the next 3 years, slowly progressive disease
– watch and wait
November 2000 presents with increased cervical, axillary, and inguinal adenopathy
– largest nodes increased to 7cm
Peripheral blood
– WBC 1,4000/µL with lymphocytosis
– Hgb 9.5g/dL
– platelets 8,9000/µL
No B symptoms, but uncomfortable with degree of adenopathy
Case study (cont’d)
Commenced on therapy with FCR
Tolerated first cycle well – notes marked decrease in lymph nodes
Returns for third cycle – notes increasing lymphadenopathy