Comments on the News
* ASH Paper: Rituximab Maintenance For a Max Of 5 Years In Follicular
Lymphoma: Randomized Phase III Trial SAKK 35/03
It seems that the favorable part of analysis
was done on a subset because of unexpected relapses early in the maintenance
arm .. but after adjusting for that (reasonable because treatment was
identical at that point) there was no difference in OS (equally good) and
toxicities (infection) appears to favor observation.
There is no significant difference in OS and in the observed best
response. Maintenance treatment was stopped due to unacceptable toxicity in
no patient in arm A vs. 3 in arm B. ... One infection grade ≥3 was reported
in arm A whereas 7 infections grade ≥3 occurred in 5 patients in arm B
(prolonged maintenance for a maximum of five years).
So we seem to be where we are with PRIMA ... better PFS but with tradeoffs
(infection and potential negative impact on subsequent therapy) and no
difference in OS at this point.
Regarding the study design: 270 patients (median age 57 years: range
25-82) with either untreated, relapsed, stable or chemotherapy resistant
follicular lymphoma of all grades were treated
I have only basic training (novice-level) in statistics as it relates to
study design, but results like this suggest that sample size has to be
larger in FL studies to account better for biologic subtypes of FL -
especially when the treatment history varies.
One school of thought is that it's unethical to do a clinical study that
cannot provide a reliable answer for the primary question (because of the
design). Increasingly, we face this problem -- an inability to do
sufficiently-powered studies because of the limited pool of patients that
are willing to enroll in trials. One way to possibly address this problem is
to raise the bar - such as requiring a bigger difference in response and
duration of response. (KarlS)
* 6 Year Follow-Up Of The
PRIMA Study of Rituximab Maintenance In previously untreated Follicular
Lymphoma Pts following Frontline r-chemo
COMMENT: It will be interesting to hear the
conversation about this report among the experts. My feeling is that this
data is more supportive of a benefit for maintenance than the data at 3
years, because the gap in PFS has not narrowed.
Overall response rate to second-line therapy 180/227 (79%) in patients from
the observation arm (CR/CRu=61%; PR=19%) versus 109/144 (76%) in patients
from the rituximab maintenance arm (CR/CRu =51%; PR=22%) (P=NS). I think the
emphasis should be on the CR rate as I feel it's the most clinically
important endpoint for subsequent therapy - but even that difference is
With a median follow-up of 73 months from randomization, 6-year progression
free survival estimate was
42.7% (95% CI 38 – 46.9%) in the observation arm
59.2% (95% CI 54.7 – 63.7%) in the rituximab maintenance arm
* J Clin Onc 2013:
Rituximab Maintenance Compared With Observation After Brief First-Line R-FND
Chemoimmunotherapy With Rituximab Consolidation in Patients Age Older
Than 60 Years With Advanced Follicular Lymphoma: A Phase III Randomized
Study by the Fondazione Italiana Linfomi.
COMMENT: In this study population with
abbreviated R-chemo maintenance Rituxan did not provide an advantage in
Progression Free Survival (PFS) - however, each group received consolidation
with Rituxan (a kind of maintenance) following the R-chemo induction.
One might speculate if consolidation with Rituxan would beat two years of
maintenance - the controversial standard set by the PRIMA trial.
Rituxan Maintenance (RM) is regularly-scheduled-therapy with Rituxan antibody
given in weekly cycles. The Rituxan might be given every 3 or 4 months
for as long as 2
years for the purpose of increasing the duration of the response to
standard therapy for lymphoma, such as Rituxan-based chemotherapy.
Rituxan Maintenance can also be given after single-agent
The potential benefits and risks seem to
vary by the type of lymphoma, and by the setting, such as if used for
follicular or aggressive lymphoma, after initial therapy, or if used in the relapse setting.
Perspectives on Rituxan Maintenance:
Summary: At this time, some experts favor
the use of Rituxan maintenance for follicular lymphoma after first
therapy with Rituxan-based chemotherapy, and others do not
(see Perspectives that follows and Pros and
Maintenance Rituxan for
Mantle Cell Lymphoma seems to be less controversial because
of recent positive findings in a study.
maintenance Rituxan is not widely used. Following
Rituxan monotherapy, observations appears to be as good as
maintenance (based on RESORT) with less cost and toxicity.
However, for marginal zone lymphoma a benefit in terms of PFS
was found in the RESORT study.
An important question is the reliability of Progression Free Survival
(PFS) as a way to measure clinical benefit in the first line
setting. PFS is a
composite endpoint that counts progression, relapse, or death as
one event. Notably, to our knowledge, there has been no significant difference in
deaths reported in the studies that have evaluated Rituxan as
maintenance compared to observation at this time (April 2013).
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Pros and Cons of Rituxan Maintenance (RM)
for indolent follicular lymphoma after Initial therapy - an
Based on the PRIMA study this use of Rituxan for
this indication delays time to relapse. CI
means confidence interval.
at 2 years: PFS (progression free survival*)
82%; CI [78-86%] for Maintenance vs.
66% CI [61-70%] for observation
3 year PFS was
78.6% (CI 74.7 - 82%) maintenance
60.3% observation arm (CI 55.8 - 64.5%)
at 6 years: PFS
59.2% (95% CI 54.7 – 63.7%) maintenance arm
42.7% (95% CI 38 – 46.9%) observation arm
Rituxan maintenance seems to increase the complete response (CR) rate, which is
associated with better long term outcomes
PFS is a composite endpoint counting
progression or mortality as an event. In this study PFS
is a measure of time to relapse only, because
there was no difference in mortality at 2 and 3 years.
Some of us will be comforted by the closer
monitoring we may receive while regular therapy on a
increases the odds of having a durable response
to first line therapy. Arguably, being in
remission without evidence of disease improves
the quality of life of the patients during this
period of time.
You may be given more treatment than is needed –
as 66%, 60%, and 43% where
in remission with observation after 2, 3, and 6 years
of follow up respectively
use of Rituxan may increase your risk for
low immunoglobulin (IG) levels with an increase in certain types of
infection (sinus, lung);
Low Ig levels may also cause
rare but very serious side effects.
Regular use of
Rituxan may lead to resistance to Rituxan-based treatment when/if treatment
is again needed and perhaps (in theory) to
radioimmunotherapy, which also targets cd20.
Resistance to Rituxan is a theoretical concern.
It might be estimated by comparing responses to
subsequent therapy with Rituxan-based therapy.
PRIMA at 6 yr:
Overall response rate (ORR) to
second-line therapy was reported as
ORR = 180/227 (79%) in observation arm
(CR/CRu=61%; PR=19%) versus
ORR = 109/144 (76%) in patients from the
rituximab maintenance arm
(CR/CRu =51%; PR=22%) (P=NS). "
Arguably, the CR rate (51% vs 61%) is the more
important outcome to monitor and compare in
order to judge the impact of maintenance on
developing treatment resistance to Rituxan-based
More treatments may require more monitoring for toxicities and
response (increasing the expense)
Maintenance increases the
cost of treatment without a study showing a
difference in outcomes in the long term (Overall
Survival). There is no difference in OS with 6 years of follow-up (PRIMA).
OS is the most reliable endpoint as it account
for all effects - known and unknown.
quickly and completely you responded to standard
treatment (given just before
maintenance) could help to
decide which is preferable for you.
difficulty with induction therapy, or a slow response, or a response that
was not complete might be a reason to choose RM.
A third option in this circumstance (a partial
response to r-chemo) is radioimmunotherapy– a
study we’d like to see done in a head-to-head
history seems to matter. The RESORT study
gave the advantage to observation for follicular
lymphoma when the initial therapy was Rituxan
x4; while the PRIMA study gave the advantage to
maintenance Rituxan when used after
Personal preference – some patients like the
idea of hitting “it” again when it’s down;
others prefer “saving bullets.” One’s anxiety
level about the chance of the lymphoma returning
sooner could be a factor.
Treating with Rituxan or other therapy as needed
could be as effective.
is not yet known if Rituxan maintenance improves survival in the
long term. More follow up time is needed in the
studies that were done.
An advantage in time to
progression does not necessarily predict a
benefit in the long term.
of Rituxan maintenance have not been evaluated
in a controlled way.
For example, 2 years of maintenance has not been
compared to 1 year.
The rate of histological
transformation did not appear to differ between
the 2 treatment arms after 6 years of follow up
Some subtypes of
indolent lymphoma may do better with maintenance
Rituxan than others.
See A subgroup analysis of small
lymphocytic and marginal zone lymphomas in the
Eastern Cooperative Oncology Group protocol
E4402 (RESORT): A randomized phase III study
comparing two different rituximab dosing
strategies for low tumor burden indolent
Patient experiences with Maintenance
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Comment on PFS, a composite endpoint – "rolling
three things into one statistic" progression, relapse, and death
from any cause.
Re: The sponsor’s website describes the
results of PRIMA:
My concern is that the sponsor
statement will be interpreted by many readers that you have a
lower chance of dying with maintenance.
"RITUXAN maintenance provided a 46% reduction in the risk of
progression, relapse, or death (p<0.0001)
I feel that the sponsor should add: However, at the time of
analysis there was no difference in the death rate between he
(Readers may not appreciate the meaning of “or.” )
Regarding the context: For indolent lymphomas we might use the
metaphor of a distance run to describe an outcome of treatment.
Here an advantage in PFS shows who is doing better after two
miles in a 10 – 12 mile run. Noting that what is “spent” early
to achieve that advantage can also be used later as needed to
help run as far as possible and that it’s not possible to know
who needs to use it – who would do as well without it.
So comparing also the duration of a remission from the end of
the respective treatment would be informative as a way to
estimate if the extra treatment is likely to improve survival –
provides clinical benefit. Coming back to the metaphor: This in
a race where virtually everyone who started it is still in it
(no difference in drop outs after 2 miles). Did the gap between
the groups of runners who received MR increase, stay the same,
or decrease after the MR was discontinued?
… Intuitively this additional analysis would help to judge if
the disease status of the patients at 2 years predicts a
survival advantage for those who had the extra treatment. This
information would help physicians and patients to make more
So I feel this is a consent / truth in advertizing issue –
noting that such interpretations of the outcomes appear to have
influenced clinical practice. Maintenance R has been widely
adopted based on this study (despite some expert disagreement on
whether it should be).
dissenting view, see Cheson: Rituximab for Follicular Lymphoma:
Maintaining an Open Mind
There is another reason for concern and that is that the
widespread use of RM in this setting has led to study proposals
seeking to build on this –using RM as the backbone and
comparator in studies testing new agents for lymphoma.
So I worry that there has been a rush to judgment on the
clinical significance of the outcomes in this study. I feel that
it needed longer follow up, and could possibly benefit from
analysis using other endpoints – such as duration of response
from end of therapy. The statement on PFS, while accurate, needs
to be clarified in respect to deaths.
Regarding the use of RM, I personally think it’s a close call –
reasons for and against maintenance, and patient preference
matters (early benefit versus risks of achieving that benefit –
and considering that 60% did as well without extra treatment.
The risks of maintenance R (MR) include: rare but fatal PML,
serious, more common but not a majority: low Ig antibodies
leading to chronic infection.
uncertainty is if using R as needed is as good with less cost
and risk (supported by RESORT study) and if MR will lead to
resistance to R when it is eventually needed again Masking a
relapse in theory could select for treatment-resistance clones.
If true, then the focus of research should be on improving
induction therapy which is harder to assess when maintenance is
added (was it induction or maintenance the provided the
improvement in the endpoint?).
Thanks for listening!
Is Progression Free Survival the Right
Endpoint for Judging the Clinical Benefit of Maintenance Rituxan
following First Therapy for Indolent Lymphoma?
An advocate's perspective
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Reports: Indolent Lymphoma -
PRIMA (Maintenance after R-chemo)
ASH - December 4, 2010: Updated Results of the PRIMA Study
Confirms the Benefit of 2-Years Rituximab Maintenance In
Follicular Lymphoma Patients Responding to Immunochemotherapy
1217 patients were enrolled from 223 centres
After a median follow-up of 36
3-year PFS (progression free survival) was
60.3% (confidence range 55.8 - 64.5%) in the observation arm and
78.6% (confidence range 74.7 - 82%) in the rituximab maintenance
Most common adverse events reported were
infections (24% and 39%) in the observation and
rituximab maintenance arms respectively. Grade
3-4 adverse events were reported in 17% of
patients in the observation arm and 24% in the
rituximab maintenance arm (neutropenia 1% vs 4%;
infections 1% vs 4%, respectively) but these
lead to treatment discontinuation in only 8 and
19 patients, respectively.
Rituximab maintenance for 2 years in patients with untreated high
tumor burden follicular lymphoma after response to immuno-chemotherapy.
PRIMA (corrected) study:
82%; confidence range 78-86% for RM vs
66% confidence range 61-70% for observation
RESORT (Maintenance after R monotherapy)
RESORT: A Randomized Phase III Study Comparing Two Different
Rituximab Dosing Strategies for Low Tumor Burden Follicular
Comments by PAL:
The results (in terms of responses and duration of response)
were encouraging with an important finding that giving
Rituxan as needed is as good as regularly scheduled maintenance
- mitigating some of the risks of this approach (by using less
Rituxan) to treating follicular lymphoma when treatment is not
Unfortunately the plot of Time to Treatment Failure (TTTF) does
not suggest a curative potential for Rituxan monotherapy.
Because there was no observation group as a control, we don't
know if the participants with ongoing remissions would have done
as well with observation - initiating first treatment when
Does the cited historical comparator of 3 years to first
treatment predict the median time to first treatment for those
with low tumor burden?
The first treatment might not necessarily be chemotherapy for
patients who wait for a need to treat.
Will the early use of Rituxan increase the risks to patients
receiving Rituxan-based chemo (such as Ig depletion and
associated infections) preclude
use of maintenance Rituxan after chemo?
ASH: Rituximab Dosing Schemes Prove Equal in Low-Burden FL
"The time to treatment failure
was about four years in those patients on a maintenance strategy
and for patients on a retreatment strategy upon relapse
A subgroup analysis of small lymphocytic and marginal zone
lymphomas in the Eastern Cooperative Oncology Group protocol
E4402 (RESORT): A randomized phase III study comparing two
different rituximab dosing strategies for low tumor burden
indolent non-Hodgkin lymphoma.
" Conclusions: A planned subgroup
analysis of non-FL pt showed significant benefit in time
to treatment failure (TTTF), and
time to first cytotoxic therapy
(TTCT) for Maintenance R but with 2 grade 4 toxicities. This
differs from the follicular lymphoma pt in this trial, for whom
response to induction was higher (70 vs. 41%; p<.0001) and where
no TTTF benefit was observed with MR. Low Tumor Burden
non-follicular indolent lymphoma pt who achieve a CR or PR to
induction R benefit from Maintenance R therapy."
JCO: Long-Term Follow-Up of Patients With Follicular
Lymphoma Receiving Single-Agent Rituximab at Two
Different Schedules in Trial SAKK 35/98
Patients (prior chemotherapy 138;
chemotherapy-naive 64) received single-agent rituximab and if
non-progressive, were randomly assigned to no further treatment
(observation) or four additional doses of rituximab given at
2-month intervals (prolonged exposure).
First line Rituxan
Single-agent rituximab as first-line and
maintenance treatment for patients with chronic lymphocytic
leukemia or small lymphocytic lymphoma: a phase II trial of the
Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May
Rituximab as first-line and maintenance therapy for
patients with indolent non-hodgkin's lymphoma.
J Clin Oncol. 2002 Oct 15;20(20):4261-7.
CONCLUSION: Rituximab is highly active and extremely well
tolerated as first-line single-agent therapy for indolent NHL.
First-line treatment with scheduled maintenance at 6-month
intervals produces high overall and complete response rates and a
longer progression-free survival (34 months) than has been
reported with a standard 4-week treatment.
Rituximab (anti-CD20 monoclonal
antibody) as consolidation of first-line CHOP chemotherapy in
patients with follicular lymphoma: a phase II study. Eur J
Haematol. 2002 Jul;69(1):21-6. PMID: 12270058 -
Reports: Indolent Lymphoma, Relapse Setting
Rituxan following R-FCM
in Relapsed follicular NHL:
JCO, 2010: Rituximab Maintenance Treatment of Relapsed/Resistant
Follicular NHL: Long-Term Outcome of the EORTC 20981 Phase III
Randomized Intergroup Study
Maintenance Rituxan following Relapse of
Rituximab long-term maintenance therapy
stem cell transplantation in patients with B-cell
ASH 2002: Proleukin® Plus Rituxan® may Reduce
Recurrences Following Stem Cell Transplant in Non-Hodgkin’s
Rituximab maintenance improves clinical outcome
of relapsed/resistant follicular non-Hodgkin's lymphoma, both in
patients with and without rituximab during induction: results of a
prospective randomized phase III intergroup trial.
2006 Jul 27;
Reports, Indolent and Relapsed settings
Overview of Studies: Rituximab maintenance therapy: a step
forward in follicular lymphoma http://bit.ly/9pncbR
Maintenance for the Treatment of Patients With Follicular Lymphoma:
Systematic Review and Meta-analysis of Randomized Trials
(free login req.)
chemotherapy and/or antibodies?
Michele Ghielmini ONCOLOGY INSTITUTE OF SOUTHERN SWITZERLAND
Extended use of Rituxan in Newly diagnosed and relapsed
Prolonged treatment with rituximab in patients with follicular
lymphoma significantly increases event-free survival and response
duration compared with the standard weekly x 4 schedule. Blood
Reports, Aggressive Lymphoma, various types and settings
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LL, 2011: Maintenance rituximab following induction
chemo-immunotherapy for mantle cell lymphoma:
follow-up of a pilot study from the Wisconsin Oncology Network.
"These long-term results suggest
that the modified R-hyperCVAD regimen with
rituximab is an excellent
option for older patients with newly diagnosed mantle cell
maintenance for DLBCL following CHOP-R? ASCO
As 6-yr FFS declined to <50% among R-CHOP responders, with or
without MR, there is a need for more effective treatment
strategies in older DLBCL pts.