stephen mulligan senior staff haematologist, royal north shore hospital; adjunct associate...
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Stephen MulliganSenior Staff Haematologist, Royal North Shore Hospital;
Adjunct Associate Professor, The University of Sydney, Australia
Senior Staff Haematologist, Royal North Shore Hospital Sydney
Adjunct Associate Professor, University of Sydney
Director of Haematology, Symbion Pathology
Founder and Chairman, Chronic Lymphocytic Leukaemia Australian Research Consortium
Royal North Shore Hospital
CLL treatment today and tomorrow: the role of rituximab
Stephen MulliganRoyal North Shore Hospital,
Sydney, Australia
CLL: indications for primary treatment
Progressive lymphocytosis– lymphocyte increase >50% in 2 months– lymphocyte doubling time <6 months
At least one of the following systemic symptoms 10% weight loss over 6 months– extreme fatigue, persistent fevers, night sweats
Progressive marrow failure (anaemia or thrombocytopenia)
Massive or progressive splenomegaly
Massive or progressive lymphadenopathy
Autoimmune cytopenias
Cheson B, et al. Blood 1996;87:4990–7Hallek M, et al. Blood 2008. In pressCLL = chronic lymphocytic leukaemia
Treatment strategies for CLL
Treatment strategy decisions are influenced by disease, patient performance status and comorbidities
Palliative approach (traditional)
– goals: obtain maximum control of symptoms, prevent complications and maintain quality of life
– multiple intermittent treatment schedules
– no survival advantage for tested treatments
Response-orientated approach
– aim for complete remission (CR)
– minimal residual disease (MRD)
– improved response may improve survival
Prognostic factors independent of disease stage
Chromosomal aberrations: 11q-, 17p-
Unmutated IgVH status
Expression of cytoplasmic ZAP-70
Short lymphocyte doubling time
Elevated serum β2 microglobulin
Elevated serum levels of soluble CD23
Elevated serum thymidine kinase activity
Leukaemia cell surface expression of CD38
Binet JL, Blood 2006;107:859–61
First-line treatment for CLL: a brief historical perspective
Alkylating agents-treatment of choice until the 1990s– chlorambucil – introduced early 1950s – cyclophosphamide, adriamycin and prednisone
(CAP)– cyclophosphamide, doxorubicin, vincristine,
prednisone (CHOP)
Fludarabine superior to chlorambucil in randomised clinical trials
Johnson S, et al. Lancet 1996;347:1432–8 Rai K, et al. N Engl J Med 2000;343:1750–7 Leporrier M, et al. Blood 2001;98:2319–25
1Eichhorst B, et al. Blood 2005;107:885–912Flinn IW, et al. J Clin Oncol 2007;25:793–8
3Catovsky D, et al. Lancet 2007;370:230–9
FC versus F
Investigator Year n ORR (%) CR (%) PFS
Eichhorst1 2006 375 94 vs 83; p=0.001
24 vs 7; p<0.001
48 vs 20 months; p=0.001
Flinn2 2007 278 74.3 vs 59.5 p=0.013
23.4 vs 4.6; p<0.001
31.6 vs 19.2 months; p<0.0001
Catovsky3 2007 390* 94 vs 80; p<0.0001
38 vs 15; p<0.0001
36% vs 10%;†
p<0.00005
*A further 387 patients were randomly assigned to receive chlorambucil†PFS at 5 yearsORR = overall response ratePFS = progression-free survival
Fludarabine plus cyclophosphamide (FC versus F) in CLL
CLL4 trial: benefit of FC over F or chlorambucil in terms of PFS
777 patients with CLL requiring treatment were randomised fludarabine (n=196), chlorambucil (n=387) or FC (194)
Overall survival (OS) PFS
Catovsky D, et al. Lancet 2007;370:230–9
100
80
60
40
20
0
Su
rviv
al (
%)
0 1 2 3 4 5Time (years)
100
80
60
40
20
0
PF
S (
%)
0 1 2 3 4 5Time (years)
Chlorambucil
FludarabineFC
Chlorambucil
Fludarabine
FCPatients Events O/E
387 116 0.9
194 71 1.1
196 67 1.0
Patients Events O/E
387 311 1.3
194 149 1.1
196 102 0.5
CD20 structure and epitope recognition
B-cell tetraspan protein
33–37kDa non-glycosylated phosphoprotein
Rituximab epitope – conformationally-
dependent and discontinuous epitope
– steric proximity with disulphide bond
From: Binder M, et al. Blood 2006;108:1975–1978 (original article) Jensen-Jarolim E, et al. Blood 2006;108:1794–1795 (commentary)
(170) ANPS (173)(182) YCYS (185)
Rituximab binding rapidly redistributes CD20 within lipid rafts
Signal transduction platforms
– microdomains enriched in cholesterol and sphingolipid
– outer membrane
– complement defence proteins
– inner membrane
– Src-family kinases
Rituximab cross-linking
– induces rapid redistribution in the plasma membrane
– modifies cell function
Cragg MS, et al. Curr Dir Autoimmun 2005;8:140–74
CD20 multitimers
Rituximab
Raft domain
Rituximab in CLL: rationale
Mechanism of action– antibody-dependent cellular cytotoxicity (ADCC)1
– complement-dependent cytotoxicity2
– induction of apoptosis3,4
Good clinical activity in combination chemotherapy– synergistic with other cytotoxics3,5
Generally well tolerated – potential for maintenance therapy
1Lefebvre ML, et al. J Immunother 2006;29:388–97; 2Golay J, et al. Blood 2001;98:3383–93Byrd J, et al. Blood 2002;99:1038–43; 4Hussain S, et al. Clin Cancer Res 2007;13:2144–50
5Alas S, et al. Clin Cancer Res 2001;7:709–23
Synergy between rituximab and fludarabine
Rituximab Increases efficacy of fludarabine and other cytotoxics
– independent of mechanism of cytotoxic action
– occurs in CLL with incomplete antigen saturation1,2 Activation of caspases and apoptosis3 Downregulates Bcl-2 and Bcl-x(L) protein4 Increased propensity to ADCC and complement activation Altered cell signalling and calcium flux
Fludarabine Prevents DNA repair of alkylating agent cross links Induction of apoptosis Down-regulates CD46, CD55, CD59 (complement defence proteins)5
1Wierda W, et al. J Clin Oncol 2005;98:3383–9; 2Chow KU, et al. Haematologica 2002;87:33–43 3Byrd J, et al. Blood 2002;99:1038–43; 4Alas S, et al. Clin Cancer Res 2001;7:709–23
5Di Gaetano N, et al. Br J Haematol 2001;114:800–09
The evolution toward immunochemotherapy for CLL
Single-agent therapy– fludarabine
Combination chemotherapy– FC
Combination with immunotherapy– rituximab plus FC (R-FC)
Single-agent rituximab is active in CLL
1O’Brien S, et al. J Clin Oncol 2001;19:2165–702Byrd J, et al. J Clin Oncol 2001;19:2153–64
3Hainsworth J, et al. J Clin Oncol 2003;21:1746–534Thomas D, et al. Blood 2001;98:364a (Abstract 1533)
Investigator Year n
Prior rituximab treatment
ORR(%)
CR(%)
Rituximab(mg/m2/wk)
O’Brien1 2001 40Yes
and no22–75 –
375 x 1500–2,250 x 3
Byrd2 2001 33Yes
and no45 3
250–375t.i.w. x 4
Hainsworth3 2003 44 No 58 9375 x 4
+ 4 x every 6 months
Thomas4 2001 31 No 90 19 375 x 8
t.i.w. = three times weekly
Rituximab + fludarabine results in improved response rates
Induction regimenCR(%)
OR(%)
2-year PFS
2-year OS
Rituximab + fludarabine
(n=104)
CALGB 9712 38 84 67 93
Fludarabine (n=178)CALGB 9011 20 63 45 81
Byrd J, et al. Blood 2005;105:49–53
OR = overall response
Byrd J, et al. Blood 2005;105:49–53
PFS OS
Pro
bab
ilit
y
Time (months)
p<0.0001
Rituximab + fludarabine (CALGB 9712)
Fludarabine (CALGB 9011)
1.0
0.8
0.6
0.4
0.2
00 20 40 60 80 100 120 140
Rituximab + fludarabine results in prolonged PFS and increased OS
Time (months)
p=0.003
Rituximab + fludarabine (CALGB 9712)
Fludarabine(CALGB 9011)
1.0
0.8
0.6
0.4
0.2
00 20 40 60 80 100 120 140
Pro
bab
ilit
y
The R-FC study at MDACC, University of Texas
November 1999–January 2004
n=300
R-FC as first-line treatment
CR rate 72%; time-to-progression (TTP) 80 months
Treated every 4 weeks to six cycles of R-FC
– rituximab 375mg/m2 day 1 cycle 1 rituximab 500mg/m2 day 1 cycles 2–6
– fludarabine 25mg/m2 days 1–3
– cyclophosphamide 250mg/m2 days 1–3
Keating M, et al. J Clin Oncol 2005;23:4079–88Tam C, et al. J Clin Oncol 2007;25(Suppl. 18):359s (Abstract 7008)
MDACC = MD Anderson Cancer Center
R-FC results in the highest OR and CR rates reported to date
Tam C, et al. J Clin Oncol 2007;25(Suppl. 18):359s (Abstract 7008)
Response Patients (n) %
CR 217 72
nPR 30 11
PR 36 12
No response 12 4
Early death 2 1
95%
nPR = nodular partial responsePR = partial response
First-line R-FC is well tolerated
Most toxicities were similar to FC
Grade 3/4 infusion-related reactions occurred in 6%
The infection rate was similar to historical FC alone
IgVH mutation status
– no effect on the CR rate – most important determinate of remission duration
• >90% mutated patients remain in CR at 5 years• unmutated patients median CR duration 5 years
Keating M, et al. J Clin Oncol 2005;23:4079–88Lin KI, et al. Blood 2007;110:232a (Abstract 753)
Tam C, et al. J Clin Oncol 2007;25(Suppl. 18):359s (Abstract 7008)
Tam C, et al. J Clin Oncol 2007;25(Suppl.18):359s (Abstract 7008)
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n
0 12 24 36 48 60 72 84 96
Months
R-FC
Patients Died Treatment
190 150 Fludarabine
140 81 FC/FM
300 68 R-FC
FC/FM
Fludarabine
} p=0.001
Improved OS with R-FC compared with historical MDACC
fludarabine-containing regimens
M = mitoxantrone
German CLL study group/international CLL8 study of FC versus R-FC
• CLL
• Binet B,C
• 18 years
• No priortherapy
• Centralhistologyreview
RANDOMISE
R-FC x 3 cycles(every 4 weeks)
FC x 3 cycles (every 4 weeks)
RESTAGING
R-FC x 3 cycles(every 4 weeks)
FC x 3 cycles (every 4 weeks)
SD, PD off study
SD = stable diseasePD = progressive disease
Recruitment closed March 2006 861 patients recruited Analysis anticipated 2008
Rituximab doseCycle 1: 375mg/m2
Cycles 2–6: 500mg/m2
Roche Media Release 25th January, 2008
Basel, 25 January 2008
http://www.roche.com/med-cor-2008-01-25
“MabThera increases the time patients with (CLL) live ... Pivotal Phase III study with MabThera reaches primary endpoint in first line treatment for patients with CLL
The pivotal CLL8 trial, initiated by the German CLL study group, successfully met its primary endpoint, by showing that patients treated with MabThera in combination with the current standard chemotherapy achieved a significant improvement in progression free survival, compared to patients treated with chemotherapy alone
The CLL8 study is an international study ... included 817 patients … at 203 study sites across 11 countries ... The study aimed to show a 35% increase in progression free survival when the MabThera-based combination was used”
Reduced dose R-FC: ‘R-FC-Lite’ 6 x 4-weekly cycles of
– fludarabine 20mg/m2 days 1–3
– cyclophosphamide 150mg/m2 days 1–3
Rituximab 500mg/m2 days 1 and 14
– rituximab-maintenance therapy 500mg/m2 every 3 months until progression
40 previously untreated patients evaluable for efficacy
– ORR 100%, CR 85%
– all CR patients CD5/19 flow negative in marrow
42 patients evaluable for safety/toxicity
– grade 3/4 neutropenia in 12% of courses
– grade 3/4 thrombocytopenia in 3% of courses
– grade 3/4 anaemia in 2.5% of courses
Tarhini T, et al. Blood 2006;108:805a (Abstract 2844)
Tumour lysis – allopurinol
HSV/CMV – valacyclovir/valganciclovir
PCP – SMX/TMP
Neutropenia – pegfilgrastim
Wierda WG, et al. Blood 2007;110:194a (Abstract 628)
*High risk CLL defined as 2M 4mg/LCFAR = cyclophosphamide, fludarabine, alemtuzumab, rituximab
CFAR frontline for high risk CLL*:doses and schedule
Drug Dose Day of course
Cyclophosphamide 200mg/m2 3–5
Fludarabine 20mg/m2 3–5
Alemtuzumab 30mg 1, 3, 5
Rituximab 375–500mg/m2 2
Response Patients (%)
CR 18 (69)
nPR 0 (0)
PR PR cytopenia PR disease
7 (27) 5 (19)
2 (8)
Non-responders 1 (4)
CFAR frontline for high risk CLL*: responses (NCI-WG) (n=26)
(96%)
Wierda WG, et al. Blood 2007;110:194a (Abstract 628)
*High risk CLL defined as 2M 4mg/LNCI-WG = National Cancer Institute – Working Group
Rituximab, pentostatin, cyclophosphamide achieves high response rates in CLL
Kay N, et al. Blood 2007;109:405–11Mena RR, et al. J Clin Oncol 2007;25 (Suppl. 18s):680s (Abstract 17508)
Study Eligibility criteria
No. of evaluable patients
CR/CRun (%)
ORn (%)
Kay et al. 2007
Previously untreated, ECOG PS 0–3
64 26 (41) 58 (91)
Mena et al. 2007
Previously treated/ treatment naïve, low-grade stage II–IV CLL
59 14 (24) 36 (61)
CRu = unconfirmed CRECOG PS = Eastern Cooperative Oncology Group performance status
International Scandinavian/Australian study in previously untreated CLL
Chlorambucil – 10mg2/day for 10 days orally
Fludarabine– 25mg2/day for 5 days i.v., or– 40mg2/day for 5 days orally
Cladribine– 5mg2/day for 5 days i.v./2 hours or sq, or– 10mg2/day for 5 days orally
All treatments repeated every 28 days x 6
n=221: chlorambucil 76, fludarabine 73, cladribine 72
Karlsson KA, et al. Blood 2007;110:194a (Abstract 630) i.v. = intravenously
TTP Time to start of second therapy
Longer response duration with cladribine versus fludarabine and high dose chlorambucil
Karlsson KA, et al. Blood 2007;110:194a (Abstract 630)
100
90
80
70
60
50
40
30
20
10
00 365 730 1,095 1,460 1,825 2,190 2,555
Days
Cu
mu
lati
ve p
rop
ort
ion
su
rviv
ing
(%
)
p=0.0003 p=0.005
Chlorambucil
Fludarabine Cladribine
Chlorambucil
Fludarabine Cladribine
0 365 730 1,095 1,460 1,825 2,190 2,555
Days
100
90
80
70
60
50
40
30
20
10
0
Cu
mu
lati
ve p
rop
ort
ion
su
rviv
ing
(%
)
6 x fludarabine phosphate:fludarabine 25mg/m², days 1–5 every 28 days
Chlorambucil(up to a maximum of 12 months):chlorambucil 0.4mg/kg body weight increasing 0.1mg up to 0.8mg/kg body weight every 15 days
Eichhorst BF, et al. Blood 2007;110:194a (Abstract 629)
DCLLSG CLL5 protocol for elderly patients with advanced CLL
CLL, >65 years, untreated, Binet stage C or symptomatic A/B
Median PFS: fludarabine 21.6 months; chlorambucil 16.2 months
Median OS: fludarabine 52.6months; chlorambucil not reached
0 12 24 36 48 60 72 84PFS in months
Cu
mu
lati
ve s
urv
ival
p=0.166
OS in months
p=0.071
Median observation time = 42.7months
Fludarabine versus chlorambucil in elderly patients: PFS and OS
Eichhorst BF, et al. Blood 2007;110:194a (Abstract 629)
1.0
0.8
0.6
0.4
0.2
0C
um
ula
tive
su
rviv
al
1.0
0.8
0.6
0.4
0.2
0
RandomChlorambucilFludarabineChlorambucil -censoredFludarabine -censored
0 12 24 36 48 60 72 84
RandomChlorambucilFludarabineChlorambucil -censoredFludarabine -censored
Chlorambucil + rituximab for patients with comorbidity (CLL208)
PI: Peter Hillmen, Andrew Pettitt
Trial outline Untreated CLL unfit for fludarabine-based therapy Chlorambucil (10mg/m2/day x 7) + rituximab (6 doses) Single arm, phase II, 50 patients in total
Trial objectives 1o: safety analysis 2o: assess response rate, MRD, PFS, OS
Timelines Investigator Meeting November 2007 – first patient recruited
Rituximab maintenance therapy: improved duration of response
Induction therapy with rituximab plus fludarabine (n=79) followed by rituximab-maintenance therapy (n=35) or not (n=13) in patients with bone marrow or peripheral blood MRD
After a median follow-up of 38 months duration of response was– significantly longer in MRD-positive patients receiving
rituximab-maintenance therapy compared with no further treatment (85% vs 20% at 5 years; p=0.0001)
– superior in the subset (n=30) of high-risk patients (CD38+, unmutated, ZAP-70+) treated with rituximab-maintenance therapy (64% [n=11] vs 13% [n=9] at 2 years; p=0.006)
4, monthly cycles of rituximab 375mg/m2 followed by 12, monthly low doses of rituximab at 150mg/m2
Del Poeta G, et al. Haematologica 2007;92 (Suppl. 1) (Abstract 0361)
Summary of rationale for rituximab in CLL
CD20 in lipid raft signal transduction platforms – Rituximab crosslinking leads to
• redistribution of CD20 in lipid rafts in plasma membrane • altered cell signalling • altered calcium flux • altered complement defence • increased propensity to ADCC and complement activation • increased apoptosis • synergistic mechanism of action with fludarabine and other
cytotoxics
Clinical evidence of synergism with fludarabine and other cytotoxics
Conclusions
Immunochemotherapy is becoming standard therapy for CLL– the CLL8 trial will provide further information – data analysis in progress, scheduled completion mid-2008
Rituximab is an eminently suitable combination partner for a variety of active agents in CLL – with purine analogues in patients with good
performance status– possibly with less aggressive cytotoxic regimens in elderly
or patients with comorbidity
Maintenance rituximab is a promising potential strategy in CLL