Spotlight on Chronic Lymphocytic Leukemia
and Indolent Non-Hodgkin's Lymphoma:
European and US Perspectives on the
Evolving Standard of Care
Bruce Cheson, MD
Mathias Rummel, MD, PhD
Professor of Medicine, Head of Hematology
Georgetown University Hospital
The Lombardi Comprehensive Cancer Center
Washington, DC
Head, Department for Hematology and
Medical Oncology
The Justus-Liebig-University Hospital
Giessen, Germany
Kanti Rai, MD
Clemens Wendtner, MD
Division of Hematology-Oncology
The Long Island Jewish Medical Center
New York, NY
Professor of Medicine, Department of Internal
Medicine and Head of Laboratory of
Molecular Biology and Immunology of CLL
The University Hospital of Cologne, Germany
GCLLSG CLL8 Phase 3 Trial
FC vs FCR
Median Observation Time = 37.7 months
CR
Median
PFS
OS
FC
FCR
(n = 409)
(n = 408)
21.8%
44.1%
< .001
32.8 mo
51.8 mo
< .001
79.0%
84.1%
.01
P
• The largest benefit for FCR was observed in Binet stage A and B
• FCR did not improve the PFS or OS of patients with a del(17p)
• FCR caused more neutropenia without increasing rate of severe infections
N = 817 (Agemed: 61 yr; Binet stage A: 5%, B: 64%, C: 32%; -17p: 8%)
Hallek M, et al. ASH 2009. Abstract 535.
Progress in CLL Therapy
F → FC/M → FCR
Overall Survival
Historical Comparison From the M.D. Anderson Cancer Center
Time, months
Tam CS, et al. Blood. 2008;112:975-980.
FC vs FCR
Patients With Rai III/IV CLL
Historical Comparison From the M.D. Anderson Cancer Center
FC
FCR
P
(n = 38)
(n = 102)
29%
66%
.001
Median PFS
36 mo
79 mo
.000
Median OS
55 mo
120 mo
.004
CR
Compared with historical patients treated with FC, FCR was
associated with significantly improved response rates and survival
Parikh SA, et al. ASCO 2010. Abstract. 6519.
GCLLSG Phase 2 Trial in Advanced CLL
Bendamustine and Rituximab as First-line Therapy
Median Observation Time = 15.4 months
BR
B (90 mg/m² on days 1 and 2)
+
R (375 mg/m² for the first cycle and
500 mg/m² for subsequent cycles)
ORR
90.9%
CR
32.7%
PR
55.5%
SD
9.1%
BR administered every 28 days (6 courses max.)
•
•
•
•
In patients with unmutated IgVH, ORR = 88.9%
In patients with a del(17p), ORR = 42.9%
Major side effects (myelosuppression and infections) were infrequent
After 18 months, PFSmed has not been reached
N = 117 (Agemed: 64 yr; Binet stage A: 11.1%, B: 41.0%, C: 47.9%)
Fischer K, et al. ASH 2009. Abstract 205.
Bendamustine-R vs R-CHOP (StiL Trial)
Randomized Phase 3 Study
B (90 mg/m2; days 1+2)
+
R (375 mg/m2; day 1)
}
every 28 days
6 cycles max.
FL=53%, MZL=14%, WM=8%, SLL=4%, MCL=17%
549 untreated
patients
randomized
Stage IV (76.9%), III (19.2%)
R (375 mg/m2; day 1→every 28 days)
+
CHOP (standard regimen, every 21 days)
6 cycles max.
FL=55%, MZL=12%, WM=8%, SLL=4%, MCL=19%
Stage IV (77.5%), III (18.6%)
N = 549
Rummel MJ, et al. ASH. 2009. Abstract 405.
Primary
Endpoint:
PFS
Bendamustine-R vs R-CHOP (StiL Trial)
Safety: Final Results
Adverse Event
B-R
R-CHOP
P
Neutropenia
grade 3+4 (%)
10.7
46.5
< .0001
Leukocytopenia
grade 3+4 (%)
12.1
38.2
< .0001
Alopecia (%)
15.0
62.0
< .0001
Infectious
complications (n)
96
127
.0025
Paresthesia (n)
18
73
< .0001
Stomatitis (n)
16
47
< .0001
Urticaria and rash (n)
42
23
.0122
N = 549 (n = 513)
Rummel MJ. ASCO 2010/ASH Joint Session.
Bendamustine-R vs R-CHOP (StiL Trial)
Efficacy: Final Results
PFS
B-R
R-CHOP
(n=260) (n=253)
P
ORR
92.7%
91.3%
NA
CR
39.6%
30.0%
.0262
B-R has the potential to become a new standard first-line treatment option
for patients with FL, MCL, and other indolent lymphoma types
N = 549 (n = 513)
Rummel MJ. ASCO 2010/ASH Joint Session.
Front-line Choices for Indolent NHL and CLL:
FC, CHOP, or Bendamustine?
Practicing physicians in the United States and
Europe are likely to use more bendamustine
in the future.
Front-line Lenalidomide
Elderly Patients With CLL
5 mg orally daily for the first 56 days → titrated
≤ 25 mg/day as tolerated in 5-mg increments
Every cycle (28 days)
N = 60
(Agemed: 71 yr; Rai stage III-IV: 30%; -17p or -11q: 33%; unmutated IgVH: 60%)
Badoux X, et al. ASCO 2010. Abstract 6508.
ORR
60%
CR
8%
nPR
8%
PR
43%
Front-line Lenalidomide and Rituximab
Patients With CLL: Early Report
Lenalidomide started at 2.5 mg/d → 5 mg and 10 mg on day 8, if tolerated
(L 21/35 days [cycle 1] → 21/28 days [cycles 2-7])
Rituximab 50 mg/m2 day 29, 325 mg/m2 day 31, 375 mg/m2 day 33 (cycle 1)
→ 375 mg/m2 weekly x 4 (cycle 2) and on day 1 (cycles 3-7)
Early results of the ongoing study suggest that lenalidomide/rituximab
immunotherapy is tolerable
N = 37 (n = 30)
(Agemed: 62 yr; Rai stage III-IV: 50%; -17p or -11q: 9%; unmutated IgVH: 50%)
James DF, et al. ASCO 2010. Abstract 6583.
Lenalidomide + Rituximab
Front-line Therapy of Indolent B-Cell NHL
Lenalidomide (20 mg orally daily; days 1-21)
+
Rituximab (375 mg/m2 IV; day 1)
}
every 28 days
6 cycles max.
L-R
ORR
86%
CR + CRu
79%
PR
7%
SD
14%
• After 6 cycles of therapy, 1 patients with FL achieved CR
• The grade 3/4 AEs included rash (6 pts), neutropenia (7 pts), myalgia (4 pts),
neuropathy (1 pt), infection (1 pt), and fatigue (1 pt), and thrombosis (1 pt)
N = 30 (n = 28; agemed: 56 yr)
Fowler N, et al. ASCO 2010. Abstract 8036.
Ofatumumab-FC in Previously Untreated CLL
Randomized, 2-Dose, Phase 2 Trial
Ofatumumab (500 mg or 1000 mg)* on day 1
+
Fludarabine (25 mg/m2 IV daily; days 1-3)
+
Cyclophosphamide (250 mg/m2 IV daily; days 1-3)
Administered every 28 days (6 courses max.)
Ofatumumab
Group A,
500 mg
Group B,
1000 mg
(n = 31)
(n = 30)
ORR
77%
73%
CR
32%
50%
*In both groups, the first dose of ofatumumab was 300 mg
• O-FC is highly active at both ofatumumab doses investigated
• AEs were manageable with no unexpected toxicities
• After 8 months, PFSmed has not been reached
N = 61 (Agemed: 56 yr; Rai stage III/IV: 39% [Gr. A], 53% [Gr. B];
-17p: 6% [Gr. A], 20% [Gr. B]; unmutated IgVH: 52% [Gr. A], 30% [Gr. B])
Wierda WG, et al. ASCO 2010. Abstract 6520.
Novel Options for Rituximab-Refractory
Patients
Another Anti-CD20 mAb Probably Not the Right
Solution
O-CHOP in Previously Untreated FL
Randomized, 2-Dose, Phase 2 Trial
Ofatumumab (1500 mg or 1000 mg)* on day 1
+
Cyclophosphamide (750 mg/m2; day 3)
+
Doxorubicin (50 mg/m2; day 3)
+
Vincristine (1.4 mg/m2; day 3)
+
Prednisolone (100 mg; days 3-7)
Ofatumumab
Group A,
1500 mg
(n = 29)
Group B,
1000 mg
(n = 29)
ORR
90%
100%
CR + CRu
69%
55%
Administered every 3 weeks (6 courses max.)
*In both groups, the first dose of ofatumumab was 300 mg
• At median follow-up of 9.7 months, high response rates achieved
• Effective across all FLIPI risk groups
• Well tolerated with no unexpected toxicities
N = 59 (n = 58; agemed: 55 yr [Gr. A], 54 yr [Gr. B};
FLIPI score 3-5: 34% [Gr. A], 38% [Gr. B])
Czuczman M, et al. ASCO 2010. Abstract 8042.
Phase 2 VERTICAL Study
VBR in Patients With Relapsed or Refractory FL
V (1.6 mg/m2 ; days 1, 8, 15, 22)
+
B (90 mg/m2 ; days 1, 2)
+
R (375 mg/m2 ; days 1, 8, 15, 22, cycle 1;
day 1, cycles 2-5)
5 (35 days) cycles max.
VBR
Preliminary
Results
ORR
84%
CR
47%
PR
37%
• The most common treatment-related AEs were primarily grade 1 and 2 and
included nausea (79%), fatigue (65%), diarrhea (57%), and vomiting (44%)
• Of the 27% pts with treatment-related PN, only 6% had grade 3 (no grade 4)
• VBR is active in this heavily pretreated, high-risk population and is
generally well tolerated
N = 63 (≥ 4 doses of R, but no V or B; 39% refractory to R; 35% high FLIPI score)
Fowler N, et al. ASH 2009. Abstract 933.
PRIMA Phase 3 Study
Rituximab Maintenance Therapy in Untreated FL
2 years of rituximab maintenance therapy after induction
immunochemotherapy in previously untreated FL significantly
improves PFS with little additional toxicity
N = 1217
Salles GA, et al. ASCO 2009. Abstract 8004.
Evolving Standard of Care
European and US Perspectives
• Cross-fertilization between the US and Europe
–
–
–
–
Europe → US: bendamustine
US → Europe: lenalidomide
Europe: large randomized trials
US: new drug development
• Strategic planning between European and
US investigators
– Avoid duplication of studies
– Move toward the more efficient development of better
treatment regimens
– Improve patient outcomes