EARLY ROUGH DRAFT
(for advisors and the patient community)
therapies for previously untreated indolent lymphoma are
effective and induce long remissions - with our without
maintenance, but there is a need to do better. The
arrival of highly active targeted agents provide fresh
new opportunities to improve on the standard approach.
expert consensus is needed regarding how to select patients for
eligibility), the choice of endpoints, and the length of follow up
-- in part because of the controversy regarding the
interpretation of the PRIMA study.*
Because the median survival of patients with untreated indolent
lymphoma is very long (8 to 14 years), Progression Free
Survival (PFS) is the endpoint used to compare the efficacy of treatment
protocols. It is, clearly, the only feasible way to
evaluate new protocols for this indication.
PFS is a
composite endpoint combining progression, relapse, or mortality
as one event - measured from the beginning of therapy.
An improvement in PFS can be a surrogate that predicts improved
survival - depending on the indication (its natural history), the magnitude of the difference
in PFS, and the offsetting symptoms, toxicities and risks. So, for example, an improvement in
PFS of 4 months for the study protocol that is much more toxic
than the comparator would not
It gets more
complicated. Sometimes, as with PRIMA, the
difference in PFS does not include a difference in survival of
the elements in PFS. So for the PRIMA study, PFS is a misnomer.
More accurately, the study showed a difference in time to
relapse or progression favoring maintenance with no difference in mortality at 3, 4,
and now 6 years.
... Absent a difference in
overall survival in the two arms of a studyl, the tradeoffs
1) the impact
of the extra treatment on quality of life (minor or substantial?), the cost of therapy
(if copay will be required when the study results are
2) the risk of having more therapy than is needed (important I
feel), the added risks (small but not trivial), and possible impact of extra therapy
on response to subsequent therapy (unknown).
That an update
to PRIMA still has not shown a survival advantage for maintenance
raises additional concern about the validity of PFS as a
surrogate for improved survival
in this setting.
* 6 Year Follow-Up Of The
PRIMA Study of Rituximab Maintenance In previously untreated Follicular
Lymphoma Pts following Frontline r-chemo
We can look forward to a lively debate among experts on
the interpretation of PRIMA at ASH this year!
(hopefully fairly) based on
experience as a caregiver
and support advocate, my sense is that a protocol that
substantially improves PFS will be desirable to many patients
independent of a survival benefit --
but only if the treatment adds minimal risk. So my
personal take on
PRIMA is that it's a toss up, a close call - and that patient
preference will decide the issue - with the caveat that informing
patients about the tradeoffs of maintenance Rituxan is challenging.
(See Pros and Cons of
As a research advocate, I feel that we need to select patients
for study going forward based on individual risk factors - or
to continue to use the PFS endpoint in similar ways but for
select types of first line therapy.
For example, it
seems that researchers can make better use of the PFS endpoint by:
novel agents with R-chemo followed by observation for all
patients who have a current need to treat.
design an improved PFS at 3 years
show which induction therapy was superior without the
offsetting/ confounding concerns that come with maintenance.
This design might be most appropriate for patients with
lower-risk indolent lymphoma - such as by selecting only patients
with PET negative results following
induction therapy. The following report seems to
support patient selection based on PET.
ASH Paper: PET Compared With CT After Rituxan Induction
Therapy In Follicular Lymphoma: National Lymphocare Study
toxic immune therapies in patients where there is no
current need to trreat.
The rationale is based on idea that immune therapy will be
more effective when the patients are treatment-naive and
have minimum tumor burden, both of which can suppress
immunity. The RESORT study can serve as a historical control
in single arm screening studies to compare time to next
treatment or time to next cytotoxic treatment. Initial
therapy might not include Rituxan or could add agents that
may enhance this active immunotherapy.
non-chemo agents (doublets/triplets) in patients with a current need to treat.
The rationale is based in part on a non-proven hope
that these patients will then respond well to initial
chemo-based protocols at relapse – roughly equivalent to
treatment-naïve patients - having not been exposed yet to
non-chemo agents (doublets/triplets) in patients with low
The rationale is based on encouraging report testing Rituxan
monotherapy showing a delay to initial chemotherapy
(RESORT). It is also based in part on a non-proven hope that these
patients will then respond well to initial chemo-based
protocols at relapse – roughly equivalent to treatment-naïve
R-chemo protocols with novel maintenance protocols in
patients with high-risk lymphoma.
with high-risk disease might be based on poor response to induction therapy (PET
positive) or based on validated biomarkers, or on Minimum
Residual Disease (MRD) status with PCR testing. The
following reports seem to support the potential of MRD as a
way to predict long term outcomes.
* ASH Paper, 2013: Minimal Residual
Disease (MRD) Predicts PFS In Mantle Cell #Lymphoma: CALGB 50403 (Alliance)
See also: PAL - MRD in
In summary, there's
a need and new opportunities to evaluate novel upfront therapies for
indolent lymphoma. Despite
the controversy to date, PFS can be an informative endpoint for
comparing novel upfront non-chemo induction therapies (AKA:
doublets/triplets) with or without maintenance, and also novel
upfront induction therapies -- without maintenance in patients with
to have a better potential to be informative about long term outcomes when testing novel maintenance therapies in patients who have an
to induction therapy - who are more likely to relapse quickly.
Noting that a response-adapted approach would reduce the risk of
over-treating patients who are likely to do well without maintenance
As the duration of
treatment increases so does the importance of understanding the
impact of the protocols on quality of life.
Cost is an
increasing concern (particularly for out of pocket costs for oral drugs*)
unless the study can demonstrate that the prolonged maintenance
also improves survival - or that the more expensive protocol is
focused on patients who are most likely to need and benefit from it.
(Arguably, maintenance therapies may be as effective if used as
needed as found for Rituxan in RESORT)
* NEJM 2013: Full Disclosure —
Out-of-Pocket Costs as Side Effects
* The ASCO
Post: IOM report
on looming crisis in cancer care and research
Residual Disease (MRD) status in a prospective study as a surrogate
for survival would be a great advance over comparing time to relapse
event for indolent lymphoma. Once validated, we might be able
to compare protocols in months instead of years - and select
patients appropriately for more sustained or novel therapeutic
PAL - MRD in the News
What many patients
want and desire is to be free of the disease and also from the burden
and risks of
treatments. Tailoring therapy to the needs of the patients
will also help to reduce health care costs overall - projected to be
an increasing problem.
I look forward to