When to start treatment for cll
Novel Treatment Options in CLL
thank you John I will be very impressed
if anyone gets that last question
correct so usually this is supposed to
be great debates and updates I guess
there's nothing to debate in CLL because
everything is resolved so hopefully I
can just have a great update here are my
disclosures so on today's agenda what I
really want to do is to sort of update
everyone on sort of the data that we
have from hash and how this really fits
in you know we have a lot of long-term
data regarding FCR from the FCR 300
which are 300 consecutive patients
treated at MD Anderson and you know
those data we have up to twelve point
eight year follow-up on those patients
we also have now from ash some
seven-year follow-up data on a Bruton
tips Phase two so some very very nice
long-term Phase two data which we won't
violate any statistical rules and
compares side-by-side but we also have
two clinical trials looking at chemo you
know therapist namely FCR compared to
ibrutinib and ibrutinib rituximab in
elderly patients and in not elderly
patients our young patients that were
also presented at the hemotoxin 2018 and
so it will be important to sort of look
at these data and decide how you want to
apply them to your practice so here's a
list of approved agents for CLL of
course we're certainly not um we're not
suffering for lack of agents but I think
we are suffering for a lack of knowledge
and how to use these agents what I
really do want to emphasize is we have
this you know 2010 cut where prior to
2010 we only had chemotherapy and chemo
immunotherapy and since 2010 there's
been array of new agents and it's
important to recognize that you know
once again we need to evaluate how we
treat our patients and how we measure
the success of our treatments so we no
longer need to measure you know our
treatment successes MRD
or in terms of depth of response but
really PFS is really what's most
important and I can foresee a future
where we can cycle patients between all
these different drugs and as long as
they don't accumulate toxicities we can
actually get patients a very very long
time into their future
so here's the FCR curves the progression
free survival and overall survival for
these 300 patients treated at MD
Anderson with FCR at standard doses and
you can see their pointer okay no
pointer sorry so you can see here that
we actually have a median PFS of 6.4
years for the population overall a
nemedian overall survival of 12 point 7
years for the population overall now a
number that is actually going to be very
important to keep in mind is the
progression free survival at twelve
point eight years of 30.9% and as it
turns out there's really been no one who
has relapsed beyond year 7.2 so it
really looks like that there's a plateau
on this curve and the question is you
know whether or not this plateau
represents a group of patients who are
cured and actually if we can identify
who these patients are and sort of use
this information in pre selecting
patients who might be at great or at
high likelihood of benefiting from FCR
so looking a little bit more at this
plateau it turns out that it's seventy
four percent of the patients on this
plateau are mutated in E globulin genes
alright so these are patients with
mutated New England genes which normally
have a good prognosis thirty point nine
percent of them will do extremely well
I'm sorry thirty point nine percent of
the population but of the mutated
immunoglobulin gene patients fifty three
point nine percent overall will actually
be free from progression at twelve point
eight years the comparison for the
unmedicated group you can see there is
eight point seven years so we now have
an ability to identify a group of
patients who have a fifty-fifty chance
of really doing extremely well with
chemo immunotherapy that's the benefits
now we got to look at the downsides
because one of the problems of course is
that we can't choose where we're gonna
be on the curve we can't choose whether
or not we're gonna be the person on the
plateau or the person not on the plateau
so first we have to look at sort of the
reproducibility so here we have the
German CLL study group which that flew
Derby and cytoxan and Rituxan compared
to flew Dara beam cyclophosphamide and
is basically the same regiment as the
MDR reg and I'm sorry
MD Anderson regiment and what you can
see here for comparison purposes because
things always seem to work out a little
better in Texas so we have a median PFS
at six point four years from the MD
Anderson group where it's four point
seven years for the German CLL study
group so I think obviously the four
point seven is probably a little closer
to the truth but and although the
follow-up is still short we certainly
would expect there still to be a plateau
in these groups of patients so what
happens to these patients and these are
the data again from the FCR 300 series
so 58% of the patients who died died
from CLL 18.4% die from other cancers
15.4% die from the Richter's
transformation that's not the incidence
of Richter's but that's 15 point 4
percent of the deaths 6 point 6 percent
of the patients die from infections
while in remission and overall 71
percent of the deaths that occurred were
in patients who are in first remission
so clearly we have to be careful in
choosing our regimen because there
certainly could be a high cost to pay
now looking at secondary cancer
specifically what we see is that there's
an 8% incidence of Richter's
transformation there is a 6.3 percent
chance of human to logic malignancy
mostly AML and then 21% risk of other
cancers excluding non-melanoma skin
cancers so I really want to focus on the
hematologic malignancies because MDS and
AML
what are grouped together as secondary
myeloid neoplasia really represent an
endgame for our patients these really
are sort of that that horrible sequelae
that we really are unlikely to get our
patients back from so we talk about
secondary MDS and AML typically being
somewhere between two and eight years
after people initiate treatment and so
one would think that you know because we
have twelve point eight years of
follow-up that maybe we actually have
seen the peak or we've seen what we
would expect one of the questions though
of course and I actually missed this
morning so I don't know if we spoke
about colonal hematopoiesis but with all
that we're learning on clonal
hematopoiesis and this sort of
bottleneck that's created in your stem
cells by something like chemotherapy you
know the question becomes you know at 70
years old these persons who had FCR
chemotherapy when they're 50 what is
going to be their risk of MDS at that
point in time there's already a
background incidence of MDS and AML in
the seven year olds honor the is this
group going to be that much higher so a
word of caution is I do expect that we
need to wait and see what those
long-term data are going to reveal and
then the other problem of course with
FCR is in those patients who progress
which will be half of the mutated
patients and 92% of the unmutated
patients median survival is actually
only 51 months and a lot of this is
because the CLL comes back very
aggressively and also the patient has
had toxicities and unable to actually
tolerate additional therapy so what
other options do we have
so the b-cell receptor kinase is you can
see the list here phosphor at nib
actually was the first one and this was
a plenary session done by jonathan
freiburg at ash in 2008 for unclear
reasons it really never went forward in
oncology and is now approved for ITP we
have our BTK inhibitors ibrutinib in a
caliber - which are both approved
XANA Brut nib should be approved shortly
and then we have our pi3 kinase
inhibitors i della Duvel Lissa and
elissa which I expect will be approved
within the next 12 months so I want to
review the phase 2 data for my Bruton
immuno this is the longest follow-up we
have on these patients treated with a
b-cell receptor kinase inhibitor and
really provides us with some helpful
information so the patient's initially
treated in what's called the 1102 study
which was the first phase 2 study were
actually in two cohorts there was a
treatment naive cohort which was over 65
years of age and then there was a
relapsed refractory cohort initially the
treatment naive cohort everyone received
420 milligrams in the relapsed
refractory cohort patients were actually
randomized side that 420 or 840 because
we very quickly saw no difference
everyone was actually converted to 420
and all the data is presented in
aggregate so what I want to point out
here these are the baseline
characteristics is that the 17p deleted
incidents in the treatment of cohorts
about 6% which is what we typically see
published 3 to 7% as the incidence of
treatment naive now interestingly in the
relapsed refractory cohort the incidence
is 34% which is also fairly consistent
with what we see published and for
comparison purposes the resonate study
which was the air Bruton a pivotal study
had an incidence of 17p deletion of 35
percent and the 116 study which was I'd
Ellis subs pivotal study had a 17 p
deletion rate of 45% and the thing I
really want people to think about as we
go forward is 17 p deletion really
dramatically increases from treatment
naive to subsequent lines of therapy and
of course the question is is how do you
get there how do you get from that 6% to
that 34% and the answer is selecting for
it with chemo immunotherapy and that's
something I think that we need to think
about I'll come back to later
so here the ibrutinib they're called the
7-year outcomes for some reason but they
give you 6-year PFS data little unclear
as to why but the treatment naive cohort
the median PFS is not reached and
the six-year PFS is 88% intent for the
relapsed/refractory court you can see
the median is 50 months and the six-year
PFS is 37% so there's definitely a
difference between relapsed CLL and
treatment naive CLL and one of the
important is going to be if there's
something that we can measure that can
help predict for the differences beyond
just number of prior therapies now I'd
like to point out that the first patient
who is that tick on the treatment naive
curve was a 17 P deleted CLL patient who
was diagnosed with a Richter's
transformation at month 8 and then the
second drop on that curve was actually a
17 P deleted CLL patient who actually
had CLL responded to the ibrutinib and
then developed progression of the CL out
but was still CLL and those were the two
17 p deleted patients in that treatment
naive cohort so I really do believe that
17 P deletion is one of the predictors
for our patients not doing well and when
we look at the relapsed refractory
cohort because of course the numbers
were much more robust you can actually
see here the difference in outcomes
reported by the interface fish
abnormalities one I want to point out is
actually subsequent studies namely an
aggregate study which I'll show you in a
sec and the resonate studies all showed
really no difference for 11q deleted
patients so really looks like 17 P
deletion is the most important predictor
for patients long term outcome on a
Bruton tip and here you can see the
integrated and analysis of three
different clinical trials including the
resonate resonate to and Helios and I
can really see that 11q deleted patients
had no worse outcome compared to non 11q
deleted patients on ibrutinib i also
want to look at now the 17 p deleted
patients because this really represents
an important question of what we're
going to be looking at so the NIH did a
phase 2 study that was consisting of
treatment naive patients there were 35
and then I'm sorry treatment naive
patients and patients who had p53
dysfunction either 17p deletion or p53
mutation so there are two groups of
these patients with abnormal tp53 the
treatment naive cohort was 35 patients
and the relapsed/refractory cohort was
16 patients overall 47 of the 51
patients had 17p deletion and 4 of the
51 patients had a tp53 mutation without
a 17 peta lesion any patients with both
were included in the 17p cohort or group
so the median follow-up for all these
patients was 57 months and the
discontinuation a discontinuation rate
for these patients was 5.8 percent
overall so this was 5.8 for the entire
group of patients on the nih cohort not
just the tp53 disfunctional patients but
that's important that definitely is you
know fly it's very different from what
we often hear published when we look at
data from anthony meadow who shows a
number closer to 23 percent and
obviously there's going to be a lot of
benefits of having one very experienced
investigator managing these patients
it's also going to be a very big
difference when you have a very
motivated group of patients who are able
to get themselves to the nih but that's
something I really want to emphasize is
that we can keep people on a Bruin tip
with some tricks that people you know
basically I think with repeated
experiences may actually develop overall
in this 17 in the tp53 cohort there were
17 progressives progressor 's v really
related to Richter's transformations and
12 were related to seal out progression
so what I really want to show here and
the important thing is the five-year PFS
for the treatment naive 17p or tp53
dysfunctional patients with 74.4% and
for the relapsed refractory patients it
was 19.4% and i think that this is sort
of an important thing to keep an eye on
because clearly these are two
of patients who both have 17p deletion
or tp53 dysfunction be--it we have very
different outcomes and I think obviously
the major difference between these two
groups which we know is just the number
of prior therapies probably translates
into other genetic changes that have
occurred sort of acquired genetic
mutations inquired you know resistant
mechanisms that the cells obtain that
sort of enable them to resist ibrutinib
and so I think that this is a very
important thing to keep in mind because
I've written up front line is gonna
really do much better than ibrutinib in
relapse disease and it's not just
because of the increase in 17p deleted
cells and I think so it's really a
combination of both the 17p deletion
being present and obviously subsequent
therapies creating other unmeasurable
avenues of resistance and then the other
thing I want to mention here is that the
adverse events over time really do
decrease and that's an important thing
obviously because we are currently
planning on having our patients on this
therapy for a long time I do want to
point out that the hypertension is the
one adverse event that seems to increase
over time so while we haven't yet seen a
peak it's about in the phase two study
here at about six years it's about 25%
now the atrial fibrillation does seem to
peak at about two years and so that
really speaks there being a biology
about the patient or a protoplasm of the
patient that sets them up for afib or
that they'll be fine and not develop
atrial fibrillation so now I want to
talk about the two studies that we cited
earlier just sort of look at chemo Mina
therapy versus ibrutinib the first is an
alliance study that looked in elderly
CLL these were patients with untreated
CLL over the age of 65 there were no
Sears score requirements so there are no
measures of comorbidity just aged over
65 patients were stratified based upon
my stage presence or absence is 17 P and
11 Q deletions and zap-70 methylation in
zap-70 methylation is not some
commercially available as we all know
there's a lot of issues as we also all
know with zapped 70 testing expression
level testing and so one of the ideas
that's being put forth by the OSU group
is that methylation where an
unmethylated unmethylated promoter
really is indicative of zap-70
positivity might be a reproducible
measure of zap70 expression so whether
or not this could actually replace the
ab 70 expression is also being tested as
part of the study what I do want
everyone to remember is the study did
include 17p deleted patients which is
part of the controversy around the study
remember these were patients who
randomized to receive benda Muhsin
Rituxan ibrutinib or ibrutinib rituximab
and of course we we already know that
patients who were 17p deleted are not
going to do well with been the Machine
rituximab so you can see there the
randomizations one two one two one and
the doses that were used and
statistically the comparisons were BR
versus i BR versus ir and i versus our
overall the patient characteristics were
fairly well balanced but i want to point
out once again is the number of 17p
deleted patients and tp53 mutation
patients so there was a significant
number of patients in this group who
didn't have 17p deletion but had tp53
dysfunction we don't know but when the
data points that will be assessed is
whether or not accounting for the 17p
deletion actually might change the
outcomes of the data overall but in
looking at PFS ibrutinib in rituximab
and ibrutinib as a single agent had a
significant improvement in 24-month
progression-free survival compared to BR
and you can see the hazard ratios there
and you can see that there was no
difference between ibrutinib and
ibrutinib rituximab
of course there was no difference in
overall survival and this is actually a
good thing because patients were allowed
to cross over onto ibrutinib if they
actually progressed within one year of
completing venomous
tok-san now a huge not a caveat but one
of the things to keep in mind is I do
believe that a lot of people who
progress after Benham us in Rituxan
would have gotten ibrutinib regardless
so even if people are progressing after
a year and are therefore our off trial
and still being followed for survival
that would likely have gotten ibrutinib
anyway and so I think what we really are
looking at is the overall survival being
you know these patients being rescued
with ibrutinib as second line that is
important to keep in mind because when
you look at the resonate to study which
was Claire missile versus ibrutinib we
actually did see an increased risk of
death in the patients who got Claire
missile first and they weren't being
rescued by the ibrutinib
so that's an important thing to keep in
mind and something that we need to
actually think about a little bit more a
ease of interest and this I think is
really one of the most important slides
to look at so previously or from the
1102 data we talked about there being a
10% risk of atrial fibrillation in the
population overall here in the B R group
it was 3% and the ibrutinib group it was
17% and the IR group was 14% and then
hypertension only grade threes were 14
29 and 34 percent for Bri and higher
respectively which is actually compared
to the 25% that was seen in the
ibrutinib Phase two data so that's
clearly a significant increase and I do
believe that a lot of what we're looking
at is an impact on age on these comorbid
or the age on these adverse events and
I'll show you the young seal all data is
comparison in a moment the other thing
that raised a lot of controversy
regarding the studies there was an
increased risk of death in the iboot
native arms now when you look at the
death overall in patients who died on
treatment or 30 days post treatment
it was 1% versus 7 vs. 7 percent for Bri
and I are respectively but of course
patients remained on ibrutinib
indefinitely until they progressed or
died
and the patients had gotten been the
muscle Rituxan for six cycles so that
would be a way that might bias sort of
what we're looking at so if we just look
at the risk of death based upon or for
the first six cycles and n 30 days post
cycle six be it been demoscene or
ibrutinib the numbers are much closer
one percent two percent versus three
percent respectively
so that would something that would
suggest that that sort of normalizes for
a lot of the concerns that people first
expressed regarding the increased rate
of death the only thing to keep in mind
is if we do worry about there being a
cardiac toxicity with ibrutinib that
might sort of be seen as this
unwitnessed or unexplained deaths and
you can see there that there were two
seven and four unwitnessed or
unexplained deaths in the Bri and I our
group's respectively so now just moving
on to the young CLL study this was done
by AE cog and patients who were
untreated and younger than 70 so 70
versus 65 had to be FCR eligible and 17p
deleted patients were excluded so that's
obviously an important difference
between these trials patients are
stratified by age performance status
stage and the presence of 70 of 11q
deletion and you can see they're
randomized to two one two ibrutinib
Rituxan or FCR that the doses there and
you can see here that there's
statistically significant improvement in
progression-free survival and overall
survival for ibrutinib rituximab as
compared to FCR and you can see the
hazard ratios and the data there now
interestingly and one of the things that
I think people will take away from this
trial and have to think about is when
you look at immunoglobulin gene
mutational status as a predictor you
know because FCR does worse with the
unmutated patients and ibrutinib does
equivalent and mutated and uh mutated we
actually see the differences magnified
in the unmutated population and they
actually do go away in the mutated
population now this is short follow-up
and of course you know
happens long-term will be important to
see but for now it looks like the
benefit of ibrutinib / FC are in the
short term really was just in the
unmutated population looking at great
three adverse events throughout you can
see here that atrial fibrillation was in
the ibrutinib hour 2.9 percent and
hypertension was seven point four
percent so really far lower than what we
saw and I really like to emphasize that
these were patients younger than 70 so
this also supports the idea that there
really is a very significant impact of
age on the development of these adverse
events and take chana felt at us a favor
and sort of lined everything up side by
side and the data that he used were a
little bit different but you can see
here the comparison between IR and the
young versus IR in the older patients
for afib being 3 to 6 percent
respectively and hypertension 7 to 34
percent respectively
so in conclusion ibrutinib better than
chemo immunotherapy overall I think
that's a debate that every physician
needs to have with themselves and with
the patient and the patient needs to
have with themselves one of the
important caveat to consider is whether
or not we should consider mutational
status when were actually having this
discussion a lot of people have actually
talked about combining both together
there is a slide that Peter home and put
together that addresses this once again
that violates all rules of statistics
and what you can see here looking at the
helio study which was B R versus Bri and
the resonate study which was I versus
both Fatuma mab the curves for I and Bri
are superimposable these are both
relapsed refractory patients and so it
really suggests that maybe the B are
added very little to the ibrutinib and
then we've focused really in the
short-term toxicities and the
differences but the ultimate question is
what are going to be the long-term
toxicity
and whether or not we actually can
predict those from this point in time so
we have twelve point eight year
follow-up for FCR and we have seven year
follow-up for ibrutinib and then you
know the question about sort of this
increased risk of death in the align
study what does it mean is it something
that we need to consider now I do
believe very much that we haven't seen
this signal earlier and it's always
important to not let one study discount
all the earlier studies but obviously
it's something we need to think about
and look into more closely and then
ultimately who decides the patient or
the physician I mean I really think we
all wear our biases on our sleeves and
most of the time the patients will
actually follow their physician and
that's just something important for all
of us to keep in mind in this day and
age but thank you
[Applause]
