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For more infomation >> Budget Debate - Video 98 - Duration: 10:41. 
- Hi, Dr. Brian Koffman, I'm a family doctor
and CLL patient here in the last hours of the American
Society of Hematology, ASH 2016 meeting in San Diego.
- Hi, I'm John Seymour from the
Peter MacCallum Cancer Center in Melbourne, Australia.
- And Melbourne was the birthplace of Venetoclax, ABT199.
And we've seen that develop and now be approved
at least in the USA.
And for the first time we're looking at some data
being published on using Venetoclax in combination
with other drugs and they looked hard at the safety,
a little, numbers were small so efficacy is hard
to comment on, but could you share what your take is,
having watched your baby grown up a little bit,
and seeing how it's doing with playing with others.
- Yes, (chuckles), yes.
So Venetoclax is a single agent.
Andrew Roberts has published that data in
the New England Journal,
so great to see that getting a high profile.
Clearly the drug is very effective,
but as always, we are wanting to optimize and enhance that.
So as a single agent the complete remission rate
with Venetoclax is 20%, which is, of the new targeted drugs,
the highest complete remission rate as a single agent.
So we're beginning from a high base, but we want more.
There's good data now with safety and effectiveness
together with Rituximab,
where the complete remission rate is now up to 51%
in the relapse.
- And Rituximab is a long-standing monoclonal antibody
that's been used in all kinds of lymphoma and in CLL
and has really enhanced the quality
of almost everything else it's been joined with, yeah?
- Correct.
There's very clear data that when combined
with other agents, chemotherapy agents,
a new antibody, obinutuzumab, or in the US,
it has the trade name Gazyva,
used to be called GA101.
So various labels.
When combined with chemotherapy,
Gazyva is a more effective antibody against CLL
than Rituximab.
Inevitably and naturally, then the desire to add
obinutuzumab, the more effective antibody,
to Venetoclax was clear.
But as with all of these things, we need to be conscious
of toxicity.
One of the concerns, a very valid, real and
manifest concern with Venetoclax is the risk of
Tumor Lysis Syndrome,
rapid, and very effective cell killing
with leading to chemical imbalances.
Obinutuzumab (Gazyva) has a similar risk
and also has a risk of infusion reactions:
chills, fevers, shakes, sometimes shortness of breath
and low oxygen levels with the first infusion.
So there was appropriate caution and care
in combining the two.
But both the US study as well as a German
cooperative group study and a study in the UK
have shown safety from combining the two together.
Where the antibody begins first, the infusion reactions
are dealt with, and then after a few weeks,
the gradual ramp up of Venetoclax is begun.
So we now have very good information that,
when done with care, with vigilance and with
attention to detail, that combination can be
given safely.
- And wasn't one of the rationales that if
the antibody is given first, it would knock down the tumor,
and we know this Tumor Lysis is based on the amount
of cancer that's killed,
so if there's less cancer, or lower tumor burden,
then there's a lower risk.
I know that you stratify your patients and whether
they're high risk or low risk for Tumor Lysis Syndrome.
So wasn't that one of the hopes, that by giving
obinutuzumab early, you could lower the risk
of Tumor Lysis later.
- Yes, correct.
That's very accurately the rationale.
Now, obinutuzumab rapidly clears the peripheral blood,
but the main bulk of disease is present within lymph nodes.
At the early time point, there isn't a dramatic reduction
in the bulk in the lymph nodes.
There's some improvement, but it's not profound.
Now the flip side, the converse element is that
a CLL cell that has obinutuzumab on its surface
has received, let's call it a flesh wound,
and it's closer to dying.
So at a given dose of Venetoclax, there may be
greater cell killing when the--
- Ah, I see where you're going with this.
- when the CLL has the antibody present.
- So, there is potentially a greater risk of
Tumor Lysis if these cells already have a mortal wound
that takes them one step closer to death.
So, we can't automatically apply the same predictors
for Tumor Lysis Syndrome when Venetoclax is given
as a single agent to the situation
where a patient's CLL may be partially killed ...
- I know, it's more on the tipping point of being able to--
- That's a good analogy.
- to be pushed over into cell death.
- Yes, so my caution here is that
for example, let's say,
because the predictors for Tumor Lysis Syndrome
with Venetoclax as a single agent
were peripheral blood lymphocyte count greater than 25,000,
or lymph nodes greater than 10 cm in diameter.
So let's say you've received your Gazyva
and you're no longer in that high risk group.
It would be reckless to assume that you are no longer
at risk for Tumor Lysis Syndrome because the playing field,
the parameters are different.
So, caution and vigilance still needs to be used.
- Thank you so much for that, I think that's a
really important point.
What kind of safety, did we find any new safety signals,
putting these together, were there any concerns,
other than what we already knew about the two drugs,
when they dance by themselves?
- Yeah, no, no clear or new safety signals.
We will need to watch neutrophil count.
Both of these...
- Those are a different white blood cell
that is not part of the CLL disease,
but can be an innocent bystander from these medications.
- And is important for protecting against infection.
In the early month of treatment with Venetoclax,
about one third of patients
will have a low neutrophil count.
When used on its own, low risk of infection.
But about 15% of patients, when treated with Gazyva,
will also have a low neutrophil count.
Again, on its own, low risk of infection.
But we need to check carefully
to see whether we may have additional risks of infection
with the two.
So, still early days, but very encouraging
that these can be given safely.
Very, very small numbers of patients,
but Barbara Eichorst, from the German group,
presented information on the peripheral blood,
not bone marrow, where 14 out of the 14 patients
treated with this combination had achieved
no detectable minimal residual disease
by this flow cytometry assay
at I believe it was week twelve,
so quite early in the treatment,
three months into the combination treatment.
- That's certainly, again, early news,
but that's amazingly exciting.
- Very encouraging.
- And I'm gonna push a little bit
because Jeff Jones presented some data,
adding ibrutinib to those.
And if you could comment a little bit about
any safety or maybe just take us through that trial
a little bit, because it was a different group of patients
who were being looked at, and safety and efficacy data,
your take on that.
- Some wonderful work from Ohio State,
and adding in a third ingredient.
So we talked about the anti-CD20 antibody,
we know about Venetoclax and this was adding
a third component, ibrutinib.
There's very good information that ibrutinib
pushes CLL cells out from the tissue compartments,
out from the lymph nodes, out from the bone marrow.
It's becoming quite clear that those locations
are not simply a passive storage site.
They are locations that nurture, stimulate and protect
the CLL cells from killing from a number of treatments,
antibody treatments, and also it's emerging
probably to Venetoclax in drugs that act through apoptosis.
So this is very strongly appealing,
that we're adding cell killing signals
that work in different ways,
but we're also removing protective shields
from these CLL cells that we predict
will make them more vulnerable to killing by these agents.
Again, very early information,
and again, only about a dozen patients treated,
so we cannot draw any conclusions about effectiveness.
But it showed the principle that these three drugs,
again, with careful sequencing, so they don't
all begin at once,
and with careful monitoring, can be delivered safely.
So it gives a platform to then allow
comparison of these approaches,
which both the German group and Peter Hillman
in the UK are doing,
and of course, we then want to see whether the effectiveness
in the real world in a patient will fulfill
what our experimental studies suggest should be
the most effective combination of drugs that
we have available.
- Any final thoughts on these combinations
and what you would say to patients from ASH 2016?
- It's an incredibly exciting and optimistic time.
The tools that we have available are unprecedented
in their precision and unprecedented in
their capacity to target key pathways in CLL.
We know that from other diseases,
that when we acquire agents
that have this degree of effectiveness on their own,
the combinations have the potential for cure.
I believe that that's a very realistic goal
to be pursuing in CLL,
and the other very appealing element for patients,
for the community, and for payers is that,
if this potential is fulfilled,
these combinations should be effective
in a time-limited delivery.
Now, whether that ends up being two years or 18 months,
or three years, of course we need to do the trials.
But the paradigm of moving away from an old drug
suppressing the disease and used forever,
is one of the other appeals of these
highly potent combinations.
- I'm with you with that.
Dr. Seymour, thanks so much for the research
that you're doing and have done and what you've done
for the CLL community.
Not just in Australia, but around the world.
Thank you so much.
- Thank you. A pleasure.
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