Musings on Progress Against
Lymphoma:
2011 Highlights, Looking ahead - our Wish list
Greetings,
I am
writing to wish everyone a happy and enriching New Year and to
reflect on what has been achieved in the fight against lymphomas and
the work that remains to be done – from my perspective at least.
First it’s important to note that optimism and
hope remain warranted, because there are so many ways to effectively
target lymphoma cells, internally but also on the cell-surface –
most famously by targeting cd20.
Further, it has proven feasible to reprogram
the cells with epigenetic therapy, such as with Romidepsin.
It also appears feasible to treat lymphomas by
targeting bystander cells in the so-called microenvironment, the
non-malignant cells which appear to aid, promote, and protect the
malignant lymphocytes. (For example, Lenalidomide is thought to be active in this
way)
... So, unlike the tried and true agents used
to treat lymphoma, there are no shortages of plausible and promising
strategies in development in clinical trials!
For new patients it’s important to note that
lymphomas, being blood cell cancers, are highly sensitive to
standard therapies … chemotherapy and radiotherapy … and it has
proven to be sensitive to biologic and targeted agents.
Perhaps we should not be in such a rush to replace the tried and
true, it might be in our best interest to recognize their strengths,
while finding ways to reduce their toxicities and enhance their
activity to achieve more cures?
Our personal history with lymphoma began in
1996, in the pre-Rituxan era. There were but two choices at the
time, chemotherapy or radiation for the treatment of the “incurable”
indolent lymphomas. We owe a personal debt to the innovators of the
new agents that were approved after Joanne was diagnosed, but
equally to the brave individuals who participated in the trials!
Joanne did not get much benefit from Rituxan, but using
radioimmunotherapy (RIT) soon after high-dose Cytoxan chemotherapy
dramatically changed the clinical course of her aggressively
behaving indolent lymphoma, which prior to that sequential therapy
relapsed quickly after each treatment – many, many times over seven
years.
So the approval of new drugs is PART of
what it takes to make progress. We need to also learn how to BEST
USE these drugs by doing Comparative Effectiveness Research (CER) –
where one approach is compared to another in a randomized controlled
study.
For example, this year at ASH an NCI-funded
study called RESORT demonstrated in a convincing way that giving
Rituxan as-needed is just as good as giving it automatically on a
regular schedule … as maintenance. Notably, in this
tax-payer-funded study, the as-needed approach also
decreased how much Rituxan was given,
nearly 4-fold:
Copying:
"The mean number of Rituxan doses/pt (including the 4 induction
doses) was
15.8 (range 5- 31) for Maintenance Rituxan and
4.5 (range 4-16) for Rituxan Retreatment (as needed)"
The findings of this CER study (about 12 years
after the approval of the drug!) should substantially reduce the
cost of health care (an increasing concern in our times) while
decreasing the amount of treatment we are exposed to in order to
achieve the same result. Importantly, using less Rituxan may also
reduce the incidence of infections, which can impair our quality of
life of course … and is also expensive to treat.
Meanwhile, the place of radioimmunotherapy
(RIT) remains uncertain. The low use of RIT persists, in my
opinion, because there’s insufficient data from head-to-head studies
against the standards of care for the indolent lymphomas (CER
missing in action). The lower-than-anticipated study of RIT in turn
influenced by the low usage. After all, why study a drug that hasn't
been a commercial success?
-- a “Catch-22.”
However, there have been signals of renewed
interest in RIT-based clinical research, which might increase
further IF*, with longer follow-up, CHOP-Bexxar proves
superior to CHOP-R as the first therapy for advanced follicular
lymphoma.
Although I wonder if this will prove to be the best possible use of RIT – if less
induction chemo might often be better than more - prior to RIT,
given the immune-mediated mechanism of RIT?
Meanwhile a gaggle of new agents are showing
promise against lymphomas in early-phase clinical trials.
Good news …yes, but this is also a “poverty of
riches,” because each new agent must compete for participants in the
same small pool of patients who participate in
trials – approximately 5%–the reason for PAL’s mission to help to
advance the routine and informed consideration of clinical trials.
2011 Highlights
·
The CALGB study comparing R-CHOP to dose-adjusted
R-EPOCH is finally close to full accrual. It may change the
standard of care for DLBCL, and help to guide therapy by molecular
characteristics of the disease – by genetic profiling.
·
The RESORT study shows that giving Rituxan as-needed
is as good as giving it on a maintenance schedule – for folks with
untreated FL with low tumor burden.
·
Brentuximab vedotin (BV) is proven to be effective
against relapsed Hodgkin lymphoma and anaplastic large cell lymphoma
(ALCL)
Will we see new versions of conjugated antibody targeting other
receptors?
Can we substitute BV for one or more of the chemo agents in the
first-line treatment of Hodgkin’s, such as the toxic Bleomycin?
·
Rituxan maintenance improves the survival of older
patients with MCL compared to interferon.
·
Bendamustine-R is supplanting R-CHOP as initial
primary therapy for the indolent lymphomas and perhaps also MCL. Is
it better than FCR in CLL/SLL … that question is being evaluated in
trials?
·
The continued advances in understanding the biology
and genetics of CLL/SLL
·
The dramatic potency of engineered t-cell therapy
demonstrated in a few patients with very advanced and refractory
CLL/SLL – which is also being explored in other advanced lymphomas
Will CAR adoptive immunotherapy be the “home run” technology we have
been waiting for?
·
The encouraging activity and safety profiles for the
new targeted agents
Will these agents lead to cures when used with standard therapies?
Will they help to manage the indolent lymphomas better as needed?
·
The encouraging durable responses for fractionated
cd22 radioimmunotherapy.
A therapy that effectively targets CD22 target could be urgently
needed due to the wide use of cd20 antibody – Rituxan, which cannot
be used indefinitely
·
The proven activity of HDAC inhibitors (epigenetic
therapy) in t-cell lymphomas
Will these agents lead to cures when used with standard therapies
first line? Will they help to manage the indolent lymphomas better
as needed?
Looking Ahead – My Wish List:
·
That patients are routinely offered an
opportunity to help evaluate new therapies that have shown a
potential to improve on standard therapies or work when standard
therapies do not, or to cure the indolent lymphoma, or to make the
curative therapies safer in the long term without compromising
efficacy
·
To rapidly evaluate newly approved targeted agents,
such as brentuximab vedotin, for the treatment of relapsed lymphoma
and to evaluate their use in first line therapy.
And that the participants also benefit by participating in the
trials!
·
To rapidly evaluate the activity and safety of other
targeted agents – and there are many
(CAL101, and the btk-inhibitor appearing to have the most
encouraging efficacy and safety of the lot so far)
And that the participants also benefit by participating in such
trials!
·
To identify biomarkers (factors in the blood or tumor
sample) that can predict the clinical course of a lymphoma in order
to guide how aggressive one needs to be with therapy and to guide
when to treat.
So we don’t over-treat or under-treat, or treat unnecessarily or too
soon.
And that the researchers collaborate and develop the standardized
procedures that are needed to do this type of research – and that
patients participate in the studies and contribute the tissue!
·
To identify biomarkers that predict response to
specific treatments in order to avoid therapies that don’t work – to
limit unproductive toxicities, which can narrow the range of future
options
And that the researchers collaborate and develop the standardized
procedures that are needed to do this type of research – and that
patients contribute the tissue!
·
To find therapies that are effective when standard
therapies are not – or in patients who cannot tolerate standard
therapies
For example, to rapidly continue to evaluate the engineered t-cell
therapy (CAR-19) and that strategies to “turn off” the t-cells when
the remission is achieved also proves feasible and reliable
Or to manage lymphomas with less toxic targeted therapies as needed.
·
To evaluate again new adaptive immunotherapy protocols
(vaccines and vaccine adjuvants) as consolidation therapies – to
help prevent relapse or delay the need for more toxic therapies.
Regrettably the idiotype vaccines have not been proven effective as
tested (no matter the hype being distributed by the one surviving
sponsor - Biovest). Patients continue to have a strong interest in
this approach – one that supports instead of impairing immunity –
and will likely participate in trials, which should not ask of them
to use sub-standard induction therapies in order to test if they
work! Perhaps low dose Lenalidomide vs. Lenalidomide (L) + vaccine
in untreated indolent who do not need treatment? Just a thought,
but L is not without its issues and risks.
·
To rapidly find new ways to assess response to
standard and investigational treatment (by imaging or blood makers)
to avoid over- or under-treating patients
For example, if biomarkers for minimal residual disease are
discovered AND validated, the test could be used to rapidly compare
the efficacy of new agents without having to wait for relapse events
– the time to progression and related endpoints that require years
to measure when evaluating treatments for the indolent lymphomas.
(Noting that it was the validation of viral load as a surrogate for
efficacy in HIV studies that contributed to the rapid advances made
against that disease.)
·
That patients and caregivers ask good questions –
including which trials to participate in – the informed questions
that are needed to make the very best doctors even better.
·
That patient advocates continue to participate in the
design of clinical trials to help make trials that prove to be “good
science and good medicine” – that will quickly lead to full
enrollment and provide reliable answers to the clinical questions,
which makes progress possible.
Yours in the fight,
Karl Schwartz
President, Patients Against Lymphoma
www.Lymphomation.org
Evidence-based information on lymphoma, independent of health
industry funding
