1. MabThera at ASH
2009
The Essential Solution
News and comments from the 51st Annual Meeting of the American Society of Hematology, New Orleans, Louisiana, USA
5–8 December 2009
Excellent results were also presented for the combination
of MabThera 500 mg/m2 with chlorambucil and with
bendamustine in first-line CLL, while in relapsed CLL high
doses of MabThera monotherapy were shown to be very
effective, inducing a high rate of complete responses even in
patients who were fludarabine refractory.
In NHL, MabThera-based therapy is established as standard
treatment for both indolent and aggressive histologies.
Several interesting studies were presented, investigating how
MabThera treatment might be optimised to achieve the best
outcome for patients.
• A randomised trial in patients with follicular lymphoma
and other indolent NHL suggested that the combination
Headlines...
of MabThera with bendamustine may be associated with
higher efficacy and lower toxicity than the currently more
widely used regimen of MabThera-CHOP.
The ASH 2009 meeting saw the presentation • A quality-of-life analysis of patients with FL receiving MabThera
of new data from the groundbreaking CLL8 trial maintenance therapy showed improvements in some of the
of MabThera 500 mg/m2 plus FC versus FC alone studied physical and psychological endpoints in patients
in 817 patients with first-line CLL. After 37.7 months’ receiving maintenance compared with observation.
follow-up, the improvement in overall survival is now • Ten-year follow-up of the GELA-LNH-98.5 study in
statistically significant. This is the first time that a elderly patients with diffuse large B-cell lymphoma
significant improvement in overall survival has been confirmed that patients treated with MabThera-CHOP
demonstrated for any regimen used in first-line live significantly longer than with CHOP alone
treatment of patients with CLL. (10-year overall survival 43.5% versus 28%, respectively;
p < 0.0001).
• MabThera, in combination with FC, improves 3-year overall
survival by almost 5%, from 82.5% with FC alone to 87.2% in the • A randomised study in patients with high-risk DLBCL
MabThera-FC arm. This difference was statistically significant showed that high-dose therapy with autologous stem cell
(p = 0.012), with a hazard ratio of 0.664 indicating a transplantation offers no advantage and is not needed for
33.6% reduction in risk of death over the 3-year period. patients treated with MabThera plus chemotherapy.
• The PFS benefit for MabThera-FC that was first described at
ASH last year also improved remarkably with longer follow-
up. Median PFS was 51.8 months in the MabThera-FC arm
compared with 32.8 months for FC alone (p < 0.001, hazard
ratio 0.563), representing a 19-month improvement in median
PFS and 43.7% reduction in risk of progression or death.
MabThera highlights from ASH2009 | page one

2. MabThera at ASH
2009
The Essential Solution
MabThera 500 mg/m2 plus chemotherapy:
Changing the natural course of CLL
MabThera 500 mg/m2 plus chemotherapy became the standard
of care in first-line CLL based on the results of the CLL8 trial,
first presented at ASH 2008.1 This trial randomised 817 patients
MabThera-FC 61.9 months
with newly diagnosed CLL requiring treatment to 6 cycles of
Binet A
fludarabine/cyclophosphamide (FC) chemotherapy alone FC 41.8 months
or to MabThera-FC. MabThera was administered at 500 mg/m , 2
0 20 40 60
reduced to 375 mg/m2 for the first cycle only. Professor Michael
Hallek, the chair of the German CLL Study Group (GCLLSG), who
presented the interim analysis in 2008, described the latest results
MabThera-FC 68.8 months
after 37.7 months’ follow-up (Hallek et al. Blood 2009; 114:Abstract
Binet B
535). The auditorium was full for what was described by the chair, FC 44.9 months
Professor Stephen Devreux, as an “historic session” on therapy
0 20 40 60
of CLL. As had been shown in the previous interim analysis,
patients in the MabThera-FC arm experienced significantly longer
progression-free survival (PFS) compared with FC alone (Median
MabThera-FC 56.8 months
PFS: 51.8 months versus 32.8 months, respectively; p < 0.001,
Binet C
hazard ratio [HR] 0.563) (Figure 1). FC 45.2 months
0 20 40 60
Median PFS (months)
MabThera-FC 51.8 months
Figure 2: PFS benefit of MabThera-FC over FC alone in patients with Binet
p < 0.001
stage A, B and C disease
19 months
He therefore concluded that MabThera-FC is superior to FC alone
FC alone 32.8 months
for the treatment of Binet stage C patients, as well as those with
stage A and B disease.
0 20 40 60
Median PFS (months) “In Binet stage C patients…we can
now see PFS curves start to separate.”
Figure 1: PFS in the CLL8 study (37.7 months’ follow-up)
Having explained the 19-month improvement in PFS and efficacy
In the interim analysis in 2008, the PFS benefit of MabThera-FC
1 in different patient subgroups achieved with MabThera-FC in this
was maintained in the subgroups of patients with Binet stage A analysis, Professor Hallek then went on to describe the most
and B disease but not, with the initial short follow-up, in those with exciting part of the data, the improvement in overall survival.
Binet stage C disease. Professor Hallek explained that a clinical
At 3 years, as would be expected for a first-line CLL population,
benefit for MabThera-FC in Binet stage C patients is now becoming
median overall survival had not been reached in either arm.
apparent in the latest analysis. Although the difference in PFS
Three-year overall survival was 87.2% in the MabThera-FC arm
in this subgroup of 239 patients still did not reach statistical
and 82.5% in the FC arm. This remarkable difference of almost 5%
significance (p = 0.081) (Figure 2), Professor Hallek described
in deaths between the two arms after a relatively short time was
how, with longer follow-up in Binet C patients, “we can now see
significant to a level of p = 0.012, and the HR of 0.664 indicates that
PFS curves start to separate”.
patients in the MabThera-FC arm had a 33.6% reduction in the risk
Professor Hallek also pointed out that other efficacy measures, of death – i.e. they were a third less likely to die during the 3-year
including complete response rate and eradication of minimal follow-up period.
residual disease, were markedly and significantly improved by
MabThera-FC compared with FC alone in Binet C patients.
MabThera highlights from ASH2009 | page two

3. MabThera at ASH
2009
The Essential Solution
“This is the first time that a randomised
trial has been able to show that a 100 ORR 90.9% ORR 89.5%
ORR 90.5% ORR 88.9%
treatment can improve the natural 80
course of CLL”
Patients (%)
60
ORR 42.9%
Professor Hallek emphasised the important and historic nature of 40
the overall survival finding, in that it demonstrates that the most
20
CR CR CR CR
effective treatment should be used in first-line CLL for the best 32.7% CR 15.8% 42.9% 0% 39.7%
long-term outcome. ”This is the first time that a randomised trial 0
All patients Trisomy 12 11q- 17p- Unmutated
has been able to show that a treatment can improve the natural (n = 110) (n = 19) (n = 21) (n = 7) IgVH
course of CLL”, he concluded. (n = 63)
Effective options for patients Figure 3: MabThera-bendamustine in first-line CLL: response rates
with CLL who are ineligible Phase II trial in 100 patients with untreated CLL considered
ineligible to receive fludarabine. The median age of patients in the
for fludarabine trial was 70.5 years. The results of an interim analysis of the first
50 patients were presented and compared with a cohort of
The progression-free and overall survival benefits of MabThera-FC
case-matched patients from a previous study of chlorambucil alone.
are achieved with an acceptable increase in toxicity compared with
The median age of patients in this study was 70.1 years. The ORR
FC alone, and physically fit patients, regardless of age, can be
of 84% compared favourably with the 66.7% response rate ob-
treated with this regimen without excessive toxicity. However,
tained with chlorambucil alone (Figure 4). CR rates could not be
some patients with comorbidities may not be physically fit enough
compared between trials because of different criteria for response
to tolerate FC chemotherapy and so other effective treatments
evaluation. Nevertheless, the 17% improvement in ORR indicates
are required. MabThera is approved in combination with any
that MabThera-chlorambucil is a safe and effective regimen.
chemotherapy for the treatment of CLL and two presentations
highlighted the efficacy of MabThera-chemotherapy combinations
other than MabThera-FC in first-line CLL.
Fischer et al. (Blood 2009; 114:Abstract 205) described the PR
100
results of a Phase II study of MabThera plus bendamustine in ORR 84% nPR
80 CR
117 patients with previously untreated CLL. In 110 evaluable ORR 66.7%
Patients (%)
patients, an overall response rate (ORR) of 90.9% was obtained, 60
with 32.7% CRs. The response rate was largely maintained across 40
different subgroups of patients with adverse genetics (Figure 3). 20
As expected, patients with 17p deletion had a lower response rate.
0
This combination was well tolerated, with grade 3/4 haematological MabThera - Chlorambucil
toxicity, including neutropenia, in only around 20% of patients. chlorambucil alone
Dr Fischer concluded that MabThera-bendamustine appeared
to have comparable efficacy to MabThera-FC in first-line CLL,
with a lower incidence of haematological toxicity in this analysis. Figure 4: Response rates to MabThera-chlorambucil or chlorambucil alone
(case-matched controls) in first-line CLL
This combination may offer the opportunity to treat more patients
with CLL with an effective regimen with improved tolerability.
The two combinations are now being compared in a randomised
study (CLL10) by the GCLLSG.
The other MabThera-chemotherapy combination studied in
first-line CLL was MabThera 500 mg/m2 plus chlorambucil
(Hillmen et al., Blood 2009; 114:Abstract 3428). This was a
MabThera highlights from ASH2009 | page three

4. MabThera at ASH
2009
The Essential Solution
MabThera-based treatment Optimising MabThera-based
options in later lines of therapy therapy in indolent NHL
For patients who experience PFS in excess of 1–2 years following While MabThera plus chemotherapy is standard treatment in
first-line therapy, re-treatment with the same or similar therapy is both first-line and relapsed follicular lymphoma (FL), a variety
often the most appropriate option at relapse, and MabThera 2
of MabThera-chemotherapy regimens have been evaluated and
500 mg/m2 plus chemotherapy is approved for treatment of CLL it is not yet established if any particular chemotherapy has an
in both the first-line and relapsed settings. However, some patients advantage over another as a combination partner for MabThera.
become refractory to standard treatment regimens and, particularly Rummel et al. (Blood 2009; 114:Abstract 405) presented data
for patients who are refractory to fludarabine, treatment options from one of the first randomised studies directly comparing two
may be limited. MabThera-chemotherapy regimens in first-line treatment of
indolent NHL. A total of 513 patients with previously untreated
Previous studies have shown that the activity of MabThera
indolent NHL including FL, mantle cell lymphoma (MCL), small
monotherapy is dose-dependent in CLL3,4 and Adiga and Wiernik
lymphocytic lymphoma, marginal zone lymphoma (MZL) and
et al. (Blood 2009; 114:Abstract 2380) presented a case series
Waldenström’s macroglobulinaemia (WM) were randomised
demonstrating activity of high-dose MabThera in patients
to treatment with MabThera-CHOP (n = 253) or MabThera-
with CLL, including relapsed and fludarabine-refractory disease.
bendamustine (n = 260). More than half of the patients (54%)
Twenty two patients with varying treatment histories were
had a diagnosis of FL.
analysed and the MabThera treatment schedule could be
dose-escalated at the treating physician’s discretion. The maximum The ORRs were above 90% and did not differ significantly between
dose given to any patient was 3000 mg/m (three patients).
2
the two regimens, but the CR rate was significantly superior for
patients in the MabThera-bendamustine arm (39.6% versus
An impressive ORR of 90.9% with 54.5% CR was obtained.
30.0%, p = 0.0262). After 34 months’ follow-up, PFS was also
Moreover, even in fludarabine-refractory patients the ORR
superior for MabThera-bendamustine (54.9 months versus
was 75% with 37.5% CR (Figure 5). Such a high CR rate in
34.8 months; p = 0.00012). PFS was also significantly longer for
fludarabine-refractory patients is uncommon, and the authors
MabThera-bendamustine in the subgroups of patients with FL,
noted that “Single-agent rituximab is at least as efficacious as
MCL and WM (Table 1).
other regimens available for treatment of fludarabine-refractory
patients, with a superior toxicity profile”.
Median PFS (months)
MabThera MabThera- p- value HR 95% CI
-benda- CHOP
100 ORR 90.9%
ORR 84.6% mustine
80 ORR 75.0% FL
NR 46.7 0.0281 0.63 0.42-0.95
(n = 279)
Patients (%)
60
MCL
32.5 22.3 0.0146 0.52 0.28-0.87
(n = 93)
40
WM
NR 34.8 0.0024 0.21 0.06-0.56
20 CR CR CR (n = 41)
54.5% 53.8% 37.5% NR = not reached
0
All patients Previously treated Fludarabine Table 1: MabThera-bendamustine versus MabThera-CHOP: PFS in
(n = 22) (n = 13) refractory subgroups
(n = 8)
Figure 5: Response to high-dose MabThera-monotherapy in a case series of “For the first time, a first-line regimen
22 patients with CLL
has been shown to improve overall
Overall, the ASH 2009 meeting was a landmark event in CLL. survival”
For the first time, a first-line regimen has been shown to improve
overall survival, while the combination of MabThera with different
chemotherapies offers additional effective treatment options.
MabThera highlights from ASH2009 | page four

5. MabThera at ASH
2009
The Essential Solution
MabThera maintenance therapy: A further study (the MAXIMA study) reported ongoing experience
with MabThera maintenance therapy after 8 cycles of MabThera-
Efficacy, safety and quality of life containing induction therapy in 545 patients with first-line or
MabThera maintenance therapy prolongs progression-free and relapsed FL (Witzens-Harig et al., Blood 2009; 114:Abstract 3756).
overall survival in patients with relapsed FL5,6 and is currently being MabThera maintenance therapy was administered every 2 months
evaluated in the first-line setting. A presentation by Walker for 2 years. A total of 1,367 of 5,367 infusions were delivered
et al. (Blood 2009; 114:Abstract 2498) considered the effects of by rapid protocol (90 minutes) without significant side effects
first-line MabThera maintenance therapy on patient quality of life, The authors reported that “there were no notable safety issues
including symptom burden and psychological symptoms. associated with rituximab maintenance therapy”.
This retrospective study compared health-related quality of life in
53 patients who received MabThera maintenance therapy with “[MabThera] maintenance treatment
84 observation patients, after any first-line treatment. All patients delivered via a rapid infusion protocol
had completed Patient Care Monitor (PCM) questionnaires during was safe and well tolerated”
induction and maintenance/observation. The PCM is a 38-item
self-report measure with six major components:
• General physical symptoms Eight cycles of MabThera-
• Treatment side effects chemotherapy remains gold-
• Acute distress
• Despair and depression
standard first-line treatment for
• Impaired ambulation DLBCL
• Impaired performance
Eight cycles of MabThera-CHOP became gold-standard treatment
The investigators found that scores for all six components were for patients with diffuse large B-cell lymphoma (DLBCL) based on
either similar or superior for patients receiving MabThera the GELA-LNH-98.5 trial in 399 elderly patients, first published
maintenance therapy versus observation, with significantly greater in 2002.7 At the ASH 2009 meeting, Professor Bertrand Coiffier
improvements in general physical symptoms (p = 0.019) and a (Blood 2009; 114:Abstract 3741) presented updated data from this
greater improvement in impaired performance. Overall there were trial with 10-year follow-up. The data showed that the benefit of
no detrimental effects of MabThera maintenance on health-related MabThera-CHOP persisted over time with continued, highly
quality of life, and the authors concluded that, “considering the significant superiority of MabThera-CHOP over CHOP alone in
clinical benefit of rituximab maintenance, these findings provide all efficacy endpoints including event-free survival (34% versus
further support for use of rituximab maintenance in patients with 19.0%), PFS (36.5% versus 20.0%), disease-free survival in
follicular lymphoma.” CR patients (64.0% versus 43.0%) and overall survival (43.5% versus
28%) (p < 0.0001 for each). The overall survival curves show
“Considering the clinical benefit of clear separation, even after 10 years’ follow-up in this elderly
patient population (Figure 6).
rituximab maintenance, these findings
provide further support for use of 1.0
rituximab maintenance in patients
0.8
with follicular lymphoma.”
Patients (%)
0.6 MabThera-CHOP 43.5%
0.4
0.2 CHOP 28.0%
p < 0.0001
0
0 2 4 6 8 10
Overall Survival (Years)
Figure 6: Overall Survival after 10 years’ follow-up in the GELA LNH-
98.5 study
MabThera highlights from ASH2009 | page five

6. MabThera at ASH
2009
The Essential Solution
While the use of MabThera-CHOP has dramatically increased MabThera- MabThera-
the cure rate in DLBCL over the last decade, efforts continue to CHOEP-14 megaCHOEP
further improve outcome, particularly in high-risk patients. One
EFS (%) 71.0 56.7
approach that has been considered is the use of high-dose therapy
with autologous stem cell transplantation (HDT/ASCT) first line.
PFS (%) 76.0 64.6
The German High-Grade Lymphoma Study Group (DSHNHL) has
conducted a randomised study to determine whether MabThera in Overall survival (%) 83.8 75.3
combination with HDT/ASCT provides any advantage over standard
MabThera-chemotherapy for young, high-risk patients, and interim Table 2: MabThera-CHOEP-14 versus MabThera-megaCHOEP:
survival endpoints
results of this study were presented by Professor Norbert Schmitz
(Blood 2009; 114:Abstract 404).
“These represent the best treatment
Patients (n = 185) aged 18–60 years with high-risk DLBCL were
randomised to treatment with MabThera in combination with
results ever reported for young,
CHOEP-14 (a modification of the standard CHOP regimen high-risk patients with aggressive
involving the addition of etoposide and 2-weekly rather than CD20-positive B-cell lymphoma”
3-weekly cycles) or a high-dose regimen (MabThera plus
megaCHOEP) with ASCT (Figure 7).
“These represent the best treatment results ever reported for
young, high-risk patients with aggressive CD20-positive B-cell
lymphoma”, said Professor Schmitz, who also suggested that, in the
MabThera 375 mg/m2 ASCT ASCT ASCT
era of MabThera-chemotherapy as standard treatment, there is no
place for HDT/ASCT in first-line treatment for DLBCL.
MegaCHOEP
MegaCHOEP
MegaCHOEP
MegaCHOEP
Young
patients
with References
1 14 22 36 43 56 64 77 96
untreated, Days
high-risk 1 15 29 43 57 71 83 99 1. Hallek M, et al. Blood 2008; 112:Abstract 325.
DLBCL
2. Eichhorst B, et al. Ann Oncol 2009; 20 (suppl 4):102–104.
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
CHOEP-14
3. Byrd J, et al. J Clin Oncol 2001; 19:2153–2164.
MegaCHOEP = cyclophosphamide 1500–6000 mg/m2, doxorubicin 70 mg/m2, vincristine 2 mg,
4. O’Brien S, et al. J Clin Oncol 2001; 19:2165–2170.
etoposide 600–1480 mg/m2, prednisone 500 mg
CHOEP-14 = cyclophosphamide 750 mg/2, doxorubicin 50 mg/m2, vincristine 2 mg, etoposide 5. van Oers MHJ, et al. Blood 2008; 112:Abstract 836.
300 mg/m2, prednisone 500 mg
6. Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.
Figure 7: MabThera-CHOEP-14 versus MabThera-megaCHOEP: study 7. Coiffier B, et al. New Engl J Med 2002; 346:235–242.
design
Professor Schmitz explained that 3-year event-free survival was
significantly superior for patients in the MabThera-CHOEP-14 arm
(71% versus 56.7%; p = 0.05). PFS and overall survival were also
superior for MabThera-CHOEP-14, but the differences were not
statistically significant (Table 2).
MabThera highlights from ASH2009 || page two
MabThera highlights from ASH2009 page six

7. MabThera at ASH
2009
The Essential Solution
MabThera highlights from ASH2009 | page seven