FEATURE
Dr. Coutre: We might not be ready to
completely let go of fludarabine, but there
is absolutely a need for newer treatment
options. When it comes right down to it,
the average CLL patient is 70 years old at
the time of diagnosis and does not need
immediate treatment, so the average CLL
patient is receiving first-time treatment in
his or her 70s. In clinical trials, however,
the average participant age is far less than
that. This gives us a skewed data set not
representative of the patients seen in daily
practice.
Many times, those clinical trial patients
were receiving BR or single-agent rituximab instead of FCR; BR was believed to be
a kinder, gentler approach, but single-agent
rituximab is not even particularly effective
as a single agent in CLL. Those are the patients for whom we need better treatment
options. The newer agents – well-tolerated
oral drugs that control the disease – fit the
bill. We will continue to learn more as we
gain more experience using the drugs in
front-line and relapsed settings, but we
know one thing for sure: Chemoimmunotherapy followed by further chemoimmunotherapy in CLL just leads to more immunosuppression and infection, and that is
how most patients die from this disease.
Dr. Smith: Absolutely, but when we think
about the optimal use of fludarabine, we
have to remember that we are talking about
treating a selective subpopulation. All
the trials suggest, again, that the risks of
short- and long-term toxicities increase as
patients age. In the appropriately selected
patient population, however, fludarabine
has a role. In the German CLL10 trial,
patients older than 65 years did not have
as good outcomes, and patients 65 years
and younger with active disease do need
treatment; that is where fludarabine-based
regimens are needed.4 I absolutely agree
that we do need new treatments, particularly for older, frailer patients, who make
up a large segment of the CLL patient
population.
From my standpoint, we should
reserve fludarabine for young, fit patients,
as they will tolerate the treatment and do
well. Older, frailer patients are not great
candidates for these regimens, and we
know that deletion 17p patients do not
do well with any type of chemoimmunotherapy, including FCR.5
When examining the data from the
studies on FCR, yes, you do have to keep in
mind that this is a carefully selected population, and their experience should not be
generalized to that of the older, more common patient that you see in daily practice.
Dr. Coutre: That is interesting, and I agree
that results from these studies may seem
impressive and encouraging, but when you
apply them to practice, you often find longer duration of myelosuppression than was
expected, leading to increased infections.
In the recent FCR-versus-BR trial, patients
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receiving FCR had a higher rate of myelosuppression, which translated to more
significant infections.4 Those infections
were not increased during therapy, but immediately after therapy. So, the prolonged
effects of these regimens are very real. If
we can avoid those in CLL treatment, that
would be beneficial.
Dr. Smith: These newer drugs are promis-
ing, but fludarabine certainly isn’t dead
yet. Sure, everyone would like to replace
fludarabine with an oral drug that leads
to durable results with minimal toxicities.
That would be wonderful. But we haven’t
found that yet. There are concerns with
these newer agents, just as there are concerns about fludarabine.
However, we’ve been using fludarabine
for 20 years and are able to address those
concerns: We know how to address myelosuppression; we can give prophylactic antivirals, antifungals, antibiotics, and growth
factors to help patients through treatment;
and patients can remain off treatment for
a prolonged period. In the German CLL10
trial, the median progression-free survival
was well over four years,4 which did not
mean that patients required treatment
then, just that they had disease progression;
they might go another couple years before
they need treatment. Patients benefit from
a very long treatment-free interval with
fludarabine-based regimens, as long as
physicians are careful about selecting and
monitoring them.
With the oral agents, we simply do not
have that experience, and we have concerns
about unusual toxicities: bleeding issues
and atrial fibrillation with ibrutinib, and
immunologic responses such as colitis with
idelalisib. We also have to consider the
cost of these new agents; they tend to be
very expensive, and because patients will
take these drugs for many years, that is a
significant cost. We have to decide if that is
feasible for everyone, especially in the case
of patients with indolent CLL who may not
need constant therapy.
Dr. Coutre: That is a relevant point, certainly
in the United States where national