Drawing First Blood
We invite two experts to debate controversial
topics in hematology and health care
Is Fludarabine Dead in CLL?
Steven Coutre, MD
Mitchell Smith, MD, PhD
Disclaimer:
The following positions were assigned
to the participants and do not
necessarily reflect ASH’s opinion, the
participants’ opinions, or what they
do in daily practice.
Agree? Disagree? We want to hear
from you! Send your thoughts and
opinions on this controversial
issue to ashclinicalnews@
hematology.org.
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ASH Clinical News
A few short years ago, fludarabine was considered the gold
standard of front-line treatment for chronic lymphocytic
leukemia (CLL), providing better
response rates than old standby,
chlorambucil. Now, in an era
of monoclonal antibodies and
targeted therapies, fludarabine
is losing its place as leader of
the pack. ASH Clinical News has
invited Steven Coutre, MD, and
Mitchell Smith, MD, PhD, to
debate the question: “Is fludarabine dead in chronic lymphocytic leukemia?” Dr. Smith will
be arguing “no,” while Dr. Coutre
will be arguing “yes.”
Steven Coutre, MD: We have had fludarabine for decades, and today, the standard
front-line treatment for chronic lymphocytic leukemia (CLL) remains chemoimmunotherapy with a fludarabine-based
regimen – fludarabine, cyclophosphamide,
and rituximab (FCR), or fludarabine,
bendamustine, and rituximab (BR).
At present, with the newer therapies (such
as the Bruton tyrosine kinase inhibitor
ibrutinib and the PI3 kinase delta inhibitor
idelalisib), we don’t have the randomized
trials comparing them with fludarabinebased regimens to give us definitive
answers about outcomes such as durable
remissions. Having said that, however,
there is enough experience with the newer
agents to have at least some qualitative
impressions.
I do think the antibody therapeutics
and the kinase inhibitors have an advantage from a side effect profile. The oral drug
ibrutinib has been extremely well-tolerated
with very favorable quality-of-life results.1
Clearly, for the average older patient with
CLL, taking a well-tolerated oral drug
is preferred to receiving an intravenous
chemotherapy drug. For better or worse,
patients do not view these types of newer
agents as “real chemotherapy,” which is
part of their allure.
It is also not hard to imagine that,
based solely on the data that we have now,
these newer drugs will likely lead to more
durable remissions, particularly with the
kinase inhibitors. But we can’t draw those
conclusions yet until we have the necessary
randomized trial data.
Mitchell Smith, MD, PhD: Fludarabine is
not for everyone. Older CLL patients’ risk
for adverse events and toxicities increases
as they age, and fludarabine-associated
toxicity might also be an issue in patients
with renal dysfunction. In younger, fitter
patients, however, we do have long-term
follow-up data showing impressive results
with fludarabine-based regimens.2 We don’t
want to completely throw out fludarabinebased regimens, because in the right
patient population they can be beneficial.
As far as the impact on patient qualityof-life, yes, fludarabine is “real chemotherapy” delivered intravenously; however, this
takes place for a defined six-month period.
With that limited, six-month regimen,
fludarabine leads to years-long survival in
some patients with CLL.
With these newer oral agents, however,
patients will have to take the drug for basi-
cally the rest of their lives, and we just do
not have long-term data. Late or unexpected toxicities are still a worry. It is a bit
premature to ask patients to commit to one
of the new oral agents.
Dr. Coutre: I would agree that the concept
of time-limited therapy with a fludarabinebased regimen can be very attractive compared with the uncertainty of long-term
use of cancer drugs, particularly for younger patients. We do have good follow-up
for at least three years with ibrutinib and
have not seen any new concerns.3 If you are
looking at a 20-year horizon of treatment
for younger patients, we are never going to
be able to answer questions about late side
effects in real time. Even with the randomized trials, those issues will take an incredibly long time to address.
I believe new agents like ibrutinib
and idelalisib will start to dominate the
second-line treatment landscape. In the
past, patients would relapse after the FCR
regimen and would just get FCR again.
When bendamustine entered the treatment
landscape, patients who relapsed were
treated with that because at least it was different. In my mind, there really isn’t a goo