Re: NEJM Articles Now Available Free Online

[Guest guest]

Thanks Pat,

Sounds silly, but just reading this article gave me the chills -- too much

excitement!

Warmest regards,

Don

>

> Hi all- Hope you're taking some time today to do something nice for yourself,

or a loved one if you're a caregiver, and celebrating National Cancer Survivor's

Day...which really should be called " International " since the celebration is

world wide.

>

> CML is getting a lot of attention this weekend, please see the information

below. We all have much to celebrate today. Tomorrow many other individuals with

cancer will also be celebrating thanks to the pioneering efforts of many people

in this group who participated in clinical trials that have made the advances

with CML possible and will lead the way for other cancer treatments. That's

worth a high five or two, isn't it?

>

> Take care,

> Pat in Phoenix

>

>

> The following articles from the New England Journal of Medicine are now

available online at http://content.nejm.org/

>

> They are also the basis for presentations this weekend at the American Society

of Clinical Oncology (ASCO) meeting in Chicago. NSCML will be providing more

information on this, but in the meantime a Google search will bring up multiple

articles on the announcements, if you're interested.

>

> 1) Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia

>

> Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to

imatinib in patients with newly diagnosed chronic-phase Philadelphia

chromosome–positive CML.

>

> 2) Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid

Leukemia

>

> In patients with newly diagnosed chronic-phase CML, dasatinib, as compared

with imatinib, induced significantly higher and faster rates of complete

cytogenetic response and major molecular response.

>

> The Journal also published an editorial on these developments:

> http://content.nejm.org/cgi/content/full/NEJMe1004430

>

> Even Better Kinase Inhibitors for Chronic Myeloid Leukemia

> L. Sawyers, M.D.

>

> The clinical success of imatinib in patients with chronic myeloid leukemia

(CML), which was first reported 9 years ago,1 catalyzed a systemwide shift in

the development of cancer drugs to include molecularly targeted therapies.

According to one recent estimate, approximately 200 such drugs are now in the

clinical-development pipeline. First approved for interferon-resistant CML,

imatinib quickly became the standard of care in patients with newly diagnosed

CML on the basis of the drug's remarkable efficacy (complete cytogenetic

remissions in some 70% of patients) with minimal toxic effects when used as

initial therapy.2 Success of that magnitude is rare in oncology.

>

> But imatinib was the first drug of its kind — an early foray into the world of

kinase inhibition when the properties of the ideal candidate drug were

completely unknown. By today's standards, imatinib has relatively low potency

and inhibits its target at micromolar rather than nanomolar concentrations. In

addition, imatinib is susceptible to resistance through a large number of

different mutations in the BCR-ABL target as a consequence of the way it binds

the BCR-ABL kinase domain, an unforeseen issue at the time of its discovery.3

>

> Two next-generation BCR-ABL kinase inhibitors, dasatinib and nilotinib,

rapidly emerged as candidates for second-line CML therapy, largely on the basis

of their activity against most, but not all, imatinib-resistant mutations in

BCR-ABL.4,5 Both compounds are more potent than imatinib, and dasatinib differs

further by binding BCR-ABL through a different conformational mechanism. As

predicted from preclinical models, both drugs proved effective in patients with

CML in whom imatinib had failed.6,7

>

> In this issue of the Journal, two studies — one by Kantarjian et al.8 and the

other by Saglio et al.9 — show that both compounds are superior to imatinib when

used as initial therapy for CML. In these randomized phase 3 studies, both

dasatinib and nilotinib were superior to imatinib after 1 year of treatment with

respect to all end points that were measured. The findings include higher rates

of complete cytogenetic remission, faster time to remission, and (most

important) reduced rates of progression to accelerated phase or blast crisis.

Some observers may argue that 1 year is too early in the comparison to claim

victory in a disease with a much longer natural history, but early, sustained

complete cytogenetic response is a validated surrogate marker for survival in

CML on the basis of previous trials of interferon. Nonetheless, the differences

between the two study groups must be revisited when longer follow-up is

available.

>

> Despite the superiority of dasatinib and nilotinib in these trials, it is

important to recognize that resistance to these newer agents, as with imatinib,

could become an issue. One key difference is that the spectrum of mutations in

BCR-ABL that are capable of causing relapse is much more limited with these

newer drugs. The most significant mechanism of treatment failure is likely to be

the T315I mutation, known as the gatekeeper, which confers resistance to all

three drugs. Although early attempts to overcome this mutation have been

disappointing, recent clinical data with the experimental drug AP24534, which

inhibits T315I BCR-ABL in models of CML,10 suggest that even tumors with this

recalcitrant mutation can be successfully treated.11

>

> Do the results reported in these trials presage the retirement of imatinib

from CML therapy, forever enshrined in the history of oncology but no longer

useful? The data regarding response and side effects in the two studies

certainly make a strong case for dasatinib or nilotinib as first-line therapy

over imatinib. All three drugs have outstanding safety profiles, but there are

modest differences in side effects that might lead patients to switch from one

drug to another. There have been associations with pleural effusions with

dasatinib, biochemical changes in liver function and QT prolongation with

nilotinib, and edema and muscle cramps with imatinib. Ironically, imatinib may

survive the challenge on the basis of economic rather than scientific factors,

since it could be available in generic form as early as 2014. With rising

pressure to balance cost and efficacy, patients and payers may be forced to

select the cheapest among three excellent treatment options.

>

> These two studies cap a remarkable decade of progress in CML therapy and, for

some, may raise the question of whether we have reached the limit of what we can

hope to achieve. We know that imatinib induces a long-lasting remission but not

a cure. Presumably, dasatinib and nilotinib will perform similarly, but with

deeper, longer-lasting remissions. But the history of cytotoxic chemotherapy

teaches us that remission — first seen in pediatric acute lymphoid leukemia and

then in Hodgkin's disease and testicular cancer — is converted to a cure only

through optimal deployment of combination therapy. The fact that CML remains

dependent on BCR-ABL even after multiple rounds of BCR-ABL–inhibitor therapy

suggests that combinations of two or three kinase inhibitors, when carefully

selected to cover all known resistance mutations, could shut off all mechanisms

of escape. In contrast to the empiricism that drove the development of

combination chemotherapy, our precise molecular understanding of resistance in

CML should rapidly point to the optimal combination of targeted agents.

Furthermore, the lessons that we have learned from CML are likely to extend to

other kinase-dependent cancers, such as gastrointestinal stromal tumors, lung

cancers with mutant epidermal growth factor receptors, and BRAF-mutant

melanomas.

>

> Many observers have argued that the war on cancer, unleashed in 1971 with the

National Cancer Act, was premature because we could not realistically expect

progress in developing effective cancer treatments without understanding the

root causes. Today our knowledge of the biologic underpinnings of cancer puts us

in a very different place. The CML studies reported here give us new perspective

on what is possible.

>

[Guest guest]

I hope our video interview with Dr. Cortes from MD at

www.patientpower.info/asco on tki's is helpful to you.

Patient Power, LLC

radio and online talk shows and news

Schorr

Founder & Host

9220 SE 68th St

Mercer Island, WA 98040-5135

(206) 232-1542

(206) 295-2196 mobile

(206) 232-0212 fax

www.patientpower.info <http://www.patientpower.info>

Follow Patient Power on Twitter at: http://twitter.com/patientpower

<http://twitter.com/patientpower>

[Guest guest]

Yes, very helpful, , thank you so much!

Here is the direct link for everyone.

http://www.patientpower.info/p2tv.asp?video=12339147 & autoplay=1

>

> I hope our video interview with Dr. Cortes from MD at

> www.patientpower.info/asco on tki's is helpful to you.

>

>

>

> Patient Power, LLC

>

> radio and online talk shows and news

>

>

>

> Schorr

>

> Founder & Host

>

> 9220 SE 68th St

>

> Mercer Island, WA 98040-5135

>

> (206) 232-1542

>

> (206) 295-2196 mobile

>

> (206) 232-0212 fax

>

>

>

> www.patientpower.info <http://www.patientpower.info>

>

> Follow Patient Power on Twitter at: http://twitter.com/patientpower

> <http://twitter.com/patientpower>

>

>

>

>

>

>