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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
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Management of relapsed CLL: why rituximab?
John GribbenSt Bartholomew’s Hospital,
Queen Mary’s School of Medicine
University of London, UK
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Introduction
Fludarabine-based therapy is the standard first-line treatment for fit patients
Ultimately, all patients treated for CLL progress and require subsequent therapy
A significant proportion of patients become fludarabine resistant
Clonal evolution is observed with accumulation of negative molecular biology features
The majority of patients are aged >65 years
Allogeneic SCT is effective in some patients with relapsed CLL– use is limited in patients with advanced age
and/or comorbidities
CLL = chronic lymphocytic leukaemia; SCT = stem cell transplantation
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Relapsed versus refractory CLL
Relapse or progression – response to therapy: PR at least, lasting more than
6 months
Fludarabine-refractory disease– no response to therapy– or progression on therapy– or progression within 6 months of completion of
fludarabine therapy
PR = partial response
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Fludarabine-based regimens for relapsed/refractory CLL
Study Regimen n
Refractory patients
(%)
OR/CRnon-refractory
(%)
OR/CR refractory
(%)
Keating et al.1 F 78 64 93/57 38/28
O’Brien et al.2 FC 74 31 80/12 39/3
Bosch et al.3 FCM 60 58 72/32 34/6
Mauro et al.4 FAND 23 61 100/78 50/29
OR = overall response;CR = complete response;A = ara-C; C = cyclophosphamide;D = dexamethasone; F = fludarabine;M = mitoxantrone; N = novantrone;
1Keating M, et al. Blood 1993;81:2878–842O’Brien SM, et al. J Clin Oncol 2001;19:1414–20
3Bosch F, et al. Br J Haematol 2002;119:976–844Mauro FR, et al. Haematologica 2002;87:926–33
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Poor prognosis of advanced, relapsed CLL
Survival (years)
Responsive to both alkylating agents and fludarabine 2–3
Alkylator refractory 1–2
Fludarabine refractory (17p-) <1
Thomas D, et al. In: Cheson B, editor. Chronic lymphoid leukemias. M Dekker, 2001. p. 275–335
There is therefore an outstanding need for more effective,feasible therapies in relapsed/refractory CLL
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Rituximab in relapsed/refractory CLL: rationale
Rituximab is an active targeted therapy that acts via CD20 to eradicate lymphoma cells
Rituximab is generally well tolerated
Rituximab demonstrates good clinical activity
Rituximab demonstrates synergistic activity with fludarabine
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R-FC for previously treated CLL: regimen and patient characteristics
179 patients with pretreated CLL
– rituximab (R) 375mg/m2 cycle 1, 500mg/m2 cycles 2–6
– F 25mg/m2 days 1–3 every 4 weeks x 6
– C 250mg/m2 days 1–3 every 4 weeks x 6
– 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
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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
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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
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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
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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
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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
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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
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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
Wierda W, et al. J Clin Oncol 2005;23:4070–8
ORR = overall response rateCAP = cyclophosphamide, doxorubicin, prednisone
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The REACH trial: R-FC versus FC in relapsed CLL
• CLL• Binet B or C• >18 years• Relapsed disease,
excluding fludarabine-refractory
RANDOMISE
R-FC every 3 weeks x 3
FC every 3 weeks x 3
RESTAGE
R-FC every 3 weeks x 3
FC every 3 weeks x 3
SD, PD off study
CR, PR
Rituximab doseCycle 1: 375mg/m2
Cycles 2–6: 500mg/m2
SD = stable disease; PD = progressive disease
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Other rituximab combinations in relapsed/refractory CLL
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Rituximab plus alemtuzumab Regimen
– rituximab 375mg/m2 (day 1) and 500mg/m2 ondays 8, 15, and 22
– alemtuzumab 15mg (days 2–7) and 30mg on days 3 and 5 of weeks 2–4
20 patients with relapsed/refractory CLL– six (30%) were refractory to both fludarabine and
alkylators– all had prior exposure to rituximab and two (10%)
had prior exposure to alemtuzumab
ORR 55%, CRR 30% Faderl S, et al. Blood 2005;106 (Abstract 2963)CRR = complete response rate
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R-FCA in relapsed CLL: treatment regimen
R 500mg/m2 on day 2*
F 25mg/m2 on days 3–5
C 250mg/m2 on days 3–5
A 30mg on days 1, 3, and 5
A R CFA CF CFA
Day Every 28 days for 6 cycles
*375mg/m² dose adjustment for cycle 1 onlyA = alemtuzumab
1 2 3 4 5
Wierda WG, et al. Blood 2006;108:31 (Abstract 2839)
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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)
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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)
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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)
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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
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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
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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
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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
Restaging after three cycles shows no response
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Autologous and allogeneic SCT for poor-risk CLL
Gribben J, et al. Blood 2005;106:4389–96
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
OS Progression-free survival
0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15
Years Years
Allogeneic
Autologous
Allogeneic
Autologous
p=0.96 p=0.04
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Sorror M, et al. J Clin Oncol 2005;23:3819–29
Outcome after reduced-intensity conditioning transplantations for CLL
Related recipients Unrelated recipients
Months after HCT
Per
cen
tag
e
100
80
60
40
20
0
Months after HCT
Per
cen
tag
e
OS
DFSNRM
Relapse-related mortality
OS
DFS
NRM
Relapse-related mortality
100
80
60
40
20
00 6 12 18 24 30 36 42 480 6 12 18 24 30 36 42 48
NRM = non-relapse mortalityDFS = disease-free survival
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FK506; short-course MTX
FC versus R-FC for non-myeloblative SCT conditioning in CLL: MD Anderson experience
Cohort 1 (1996–1999): FC
Day –13 –5 –4 –3 0 +8
Rituximab 1,000mg/m2 Fludarabine 30mg/m2
Cyclophosphamide 750mg/m2
Cohort 2 (2000–2002): R-FC
Day –13 –6 –5 –4 –3 0 +1 +8
FK506; short-course MTX
Khouri IF, et al. Exp Hematol 2004;32:28–35MTX = methotrexate
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FC versus R-FC for NST conditioningin CLL: outcome (MD Anderson)
FC R-FC p value
n 7 10
2-year REL (%) 14 20 ns
2-year OS (%) 57 100 0.03
ext. chr. GVHD (%) 81 36 0.04
2-year TRM (%) 43 0 0.03
Khouri IF, et al. Exp Hematol 2004;32:28–35
REL =relapse rate; ns = not significantext. chr. = extensive chronicGVHD = graft versus host diseaseTRM = treatment-related mortality
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Allogeneic transplantation for relapsed/refractory CLL
CLL transplant consensus Allogeneic SCT is a reasonable treatment option for
younger patients with– non-response or early relapse (<12 months)
after purine analogue-based therapy– relapse <24 months after purine analogue
combinations or auto-SCT (plus high-risk genetics)– p53 mutation with treatment indication
Dreger P, et al. Leukemia 2007;21:12–17
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Case study: outcome
Underwent RIC allogeneic transplant fromHLA-matched unrelated donor
Early withdrawal of immunosuppressive therapy because of disease – concomitant with development of GVHD – good
evidence of GVL effect
Remains in CR – now 5 years post transplant
RIC = reduced-intensity conditioning GVL = graft versus leukaemia
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Case study: tumour burden after non-myeloablative allogeneic SCT
1E+07
1E+06
1E+05
1E+04
1E+03
1E+02
1E+01
1E+00
GVHD grade 3 skin
IgH
/GA
PD
H c
op
y n
um
ber
12 months post SCT
Limit of detection
0 3 6 9 48
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Conclusions
Immunochemotherapy is becoming standard treatment for relapsed/refractory CLL– the REACH trial will provide further information
Allogeneic SCT is an option for selected patients
Best supportive care and the testing of novel therapies remain very important for relapsed/refractory CLL patients