Hello
All,
As promised here is
part II
Before getting into
part II I did want to mention another milestone that was celebrated at our
meeting.
We all signed a card
and celebrated Suzan McNamara's birthday. A significant date for us all -
since it was also the date 6 years ago that Suzan received the word from
Novartis regarding the petition.
Dr. Laneuville spoke
to us about a CML registry that has been approved for Canada. This will be
quite helpful to all of us as information on every patient will be entered into
the database - blinded of course. All sorts of information will be
tracked, for instance a Hem/Onc could query the data for all patients with low
Hgb to determine if it is of any prognostic value. As you can imagine lots
of information could be tracked and queried. Hopefully we'll hear more
about this in the future.
Now for Dr.
Ravandi's part of the talk.
Most of my notes are
from the oncology conference he spoke at here in Montreal the day before meeting
with us, but then again, he presented much of the same thing. If anyone
who attended wants to add anything here, please feel free to do
so.
Dr. Ravandi also
covered the history and origin of CML, and presented more data from the IRIS
trial and the from information at MDACC.
Dr. R. spoke about
BCR ABL:
It is a tyrosine
kinase oncoprotein
Auto and substrate
phosphorylation
Highly plastic
structure
"open" active versus
"closed" autoinhibited state ( IM binds only to the active
form)
State regulated
intra-and extra-molecularly
In speaking about
Gleevec - Dr. R. said:
other kinases
inhibited by IM are:
ABL
Bcr-Abl
PDGFRβ
c-Kit
IM in the Phase I trial
With 25-85 mg/day - only 1 patient out of 10 achieved a CHR
(complete hematological remission - meaning blood counts were
alright)
140-250 mg/day- 10 patients out of 19 (53%) achieved CHR and 2
patients out of 19 (11%) achieved CCR
300-1000 mg/day - 53 patients out of 54 (98%) achieved CHR and
29 (54%) patients out of 54 achieved cytogenetic
response
17 (31%) patients of the 54 achieved Major cytogenetic
response
No MTD (maximum total dose/day) was
reached.
He also covered the results of the IRIS trial, which was
covered already by Dr. L.
Dr. R. presented data on survival with IM in newly dxed CML
comparing results with IRIS to MDACC
IRIS had 553 patients and 51 months out - ~ 95% were still
alive
MDACC had 247 patients and ~ 98% were still
alive.
He showed data that was presented at ASH last
year showing BCR-ABL levels continue to decrease with IM therapy in CP CML
(28 pts on IRIS study Rx with IM 400 mg/d
12 mos median log reduction was 3.0 and 46% had a 3 log or
better and 4% had a 4 log or better reduction
24 mos median log reduction was 3.4 and 68% had a 3 log or
better and 7% had a 4 log or better reduction
36 mos median log reduction was 3.9 and 71% had a 3 log or
better and 32% had a 4 log or better reduction
42 mos median log reductions was 4.2 and 71% had a 3 log or
better and 54% had a 4 log or better reduction
Looking at IM 400mg versus 800 mg (presented at ASH 2004
also)
Of 175 patients chosen for the higher dose, 156 achieved
Complete cytogenetic response
of the 50 patients chosen for the lower dose 39 achieved
CCR
It is important to note that this was not a randomized
trial. That is why the Gleem trial is happening in Canada, as a randomized
trial is needed to prove the higher dose
strategy/theory.
The RIGHT study looked at various doses of IM - 300mg,
400mg, 600mg and 800mg
It had the following endpoints:
Primary: Percent of patients achieving molecular
response
Secondary: time to hematologic response, cytogenetic
response, and complete molecular response
- percent of patients with undetectable BCR-ABL
transcripts at 12 mos
- Safety
Interestingly this study also showed the level of non
compliance (as it were) in that it showed actual dose of IM over time. In
the first 3 mos all patients were completely compliant at 3 mos - 36 patients
were still at 800mg, 8 were at 600mg and 3 were at 400mg, by 9 mos, 15 were at
800mg, 5 were at 600mg and 5 were at 400mg, by 12 mos, 7 were at 800mg, 1 was at
600mg and 3 was at 400mg.
The results of the trial showed that 7 of the 11 patients who
stayed at the 800mg dose achieved either a 3 log reduction or better and all 7
also achieved undetectable. So I guess there is something to be said about
compliance!
He spoke about mechanisms of "resistance" to IM (Bcr-Abl
mediated or not)
- Patient not taking drug
- ABL point mutations going to conformation change of ATP
binding site or modulators
- Increase in BCR-ABL, showing BCR-ABL kinase
activity
- Metabolic, PK, drug interactions MDR clonal
evolution
- ? other kinases - VEGF, mTOR, src
- CML no longer the main
problem
Speaking about AMN107:
Showing the molecular structure he stated that AMN107 has a
better interaction between ABL binding - improves the affinity
of BCR-ABL to bind with AMN107.
The conclusions from the Phase I trial of AMN107
are:
Hematologic response rates >50% in AP and
BP
Cytogenetic responses in AP and BP
No DLT (dose limiting toxicity)
found
Well
tolerated up to 1,200 mg daily
Rare liver, skin, or marrow AE's
(adverse events)
He spoke about Dasatinib - reviewing Talpaz's work presented
at ASH last year:
Of the 10 patients in BP, 50% achieved CHR, 80% achieved
MHR
Of the 32 patients in AP/ALL 28% achieved CHR, 69% achieved
MHR
In the same group of CML AP/BP the CG response was as
follows:
AP - 40% achieved CyR, 30% achieved CCyR, and 10% achieved
PCyR
BP - 56% achieved CyR, 10% achieved CCyR, and 16% achieved
PCyR
Of the most commonly reported non
hematologic responses:
Elevated ALT (28%)
Elevated Creatinine (23%)
Diarrhea (18%)
Paresthesia (10%)
Headache (10%)
Nausea (5%)
Peripheral edema (5%)
Pleural Effusion (3%)
GI Hemorrhage (0)
These were of low grad 1 - 2
Note: we have heard more about pleural effusion in the
current trials, so it will be interesting to see how this gets updated at this
years ASH.
He spoke about other things in the works such as Vaccines and
things, but only briefly so. I think I'll get much more information at
ASH.
We finished off by presenting Dr. Ravandi with a Moose so he
could tell all his friends he went Moose hunting in
Canada.
I have to tell you this though, as I mentioned he had
presented to a bunch of oncs the day before, he mentioned he got much better
questions from our patient audience than from the docs that he presented
to. He was very impressed with our level of
knowledge.
We thoroughly enjoyed his
company.
Stay tuned for big news on more meetings coming in the
future.
Cheers,
Cheryl-Anne
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