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


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


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


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