PONATINIB EFFECTIVE FOR T315I CML

December 6, 2010 (Orlando, Florida) — The results are preliminary, but a new tyrosine kinase online pharmacy has shown promise in patients with refractory hematologic malignancies. The investigational agent, ponatinib (developed by ARIAD Pharmaceuticals), is a potent pan-BCR-ABL inhibitor that has demonstrated activity against all tested mutants that are resistant to imatinib (Gleevec), including T315I, for which there is currently no available therapy.

There have been tremendous advances in the treatment of chronic myeloid leukemia (CML) with the advent of first- and second-generation tyrosine kinase inhibitors, explained lead author Jorge Cortes, MD, who presented the findings here at the American Society of Hematology 52nd Annual Meeting.

"Imatinib is a great drug and we have excellent second-line therapies," said Dr. Cortes, who is deputy chair and professor of medicine in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston. "Moving these drugs forward into the front line has further improved outcomes."

However, a number of CML patients will fail these therapies or develop resistance. One reason is the development of the T315I mutation; CML cells that harbor this mutation are resistant to all of the currently available drugs that target BCR-ABL.

Currently, there are no effective treatment options for patients with a T315I mutation. Preclinical research has demonstrated that ponatinib can inhibit the entire spectrum of mutations that cause resistance to other BCR-ABL inhibitors, Dr. Cortes explained.

"Ponatinib can also prevent the emergence of cells that have resistance and mutations," he said, citing findings from experimental trials. "So this can be a very valuable drug for these patients."

In addition to the T3151 mutation, ponatinib has demonstrated potent activity against an array of BCR-ABL variants, and also targets other therapeutically relevant kinases. These include inhibition of FLT3, FGF, VEGF and PDGF, and c-KIT.

Major Responses Seen

Dr. Cortes and colleagues conducted a dose-escalation phase 1 multicenter trial to evaluate the safety of ponatinib and to establish a recommended dose. They also assessed evidence of antileukemic activity in a cohort of patients with refractory hematologic malignancies.

The cohort was comprised of 74 patients, the majority of whom had CML (n = 60; 44 chronic, 7 accelerated, 9 blast phase). In addition, there were 4 patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), 8 with acute myeloid leukemia, and 4 with other hematologic malignancies.

Previous therapies received by all CML/Ph+ patients included imatinib (97%), dasatinib (Sprycel) (90%), and nilotinib (Tasigna) (57%). Nearly all of the patients (95%) had failed at least 2 previous therapies, and 65% had failed at least 3 tyrosine kinase inhibitors.

Approximately three quarters of the patients (72%) had BCR-ABL mutations at study entry. Of this group, 18 (38%) had T315I mutations, 7 (11%) had F317L mutations, and 4 (6%) had G250E mutations. Forty patients (63%) had 1 or more mutations, and 5 patients (8%) had 2 or more.

The drug was well tolerated, and the 45 mg dose was chosen as the recommended dose for further study, Dr. Cortes said. "Very importantly, we saw an excellent rate of response. About two thirds of patients achieved a major cytogenetic response, with about half of the patients achieving a complete cytogenetic response."

Of 9 evaluable patients in chronic-phase CML with T3151 mutations, 100% achieved a complete hematologic response, 100% achieved a major cytogenetic response, and 89% (n = 8) achieved a complete cytogenetic response. Overall, for the 38 evaluable patients in chronic-phase CML, 95% achieved a complete hematologic response, 66% a major cytogenetic response, and 53% a complete cytogenetic response.

The results for patients in accelerated and blast-phase CML, and in those with Ph+ ALL, were less striking. There were no complete hematologic responses, and only 35% achieved a major hematologic response. A major cytogenetic response was achieved by 24%, and a complete cytogenetic response was achieved by 12%. In the subgroup with T3151 mutations, 20% achieved a major hematologic response and 20% achieved a major cytogenetic response. There were no complete responses.

"These are very exciting responses in these patients," Dr. Cortes noted.

The toxicity profile of ponatinib was acceptable, he added. The most common adverse events observed were thrombocytopenia (24%), headache (14%), nausea (14%), arthralgia (13%), fatigue (13%), anemia (11%), increased lipase (11%), muscle spasms (11%), rash (11%), myalgia (10%), and pancreatitis (10%). At a dose of 60 mg, dose-limiting toxicities (elevated pancreatic enzymes and pancreatitis) were reported in 4 of 14 patients.

Is Imatinib Obsolete?

This is an important study, said Karen Ballen, MD, clinical director of the leukemia program at Massachusetts General Hospital Cancer Center in Boston.

"Even though the results are preliminary, the data are promising for patients who have no other options," said Dr. Ballen, who was not involved in the study.

The researchers are now moving ahead with a phase 2 trial, which was initiated in September 2010.

"As we get first-, second-, third-generation drugs — hopefully, the next generations are better than the old ones," said Peter Emanuel, MD, director of the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock. "The question is: Will imatinib eventually become a historical drug?"

Dr. Emanuel was not involved in the study; he moderated a press briefing in which the highlights of the study were presented.

Dr. Cortes reports receiving research funding from ARIAD, ChemGenex, and Deciphera. Dr. Emanuel reports relationships with Bristol Myers Squibb, Novartis, and Genzyme

American Society of Hematology (ASH) 52nd Annual Meeting. Abstract 210. Presented December 6, 2010.

Penis Enlargement

It’s not uncommon for men to desire a larger penile erection, and such a desire is natural and nothing to be ashamed of. Unfortunately, many men are not able to achieve a large, hardened erection, no matter how aroused they become. The reasons for this are sometimes medical, but it has been found that in the majority of cases, the cause could simply be age, stress, and even poor circulation.

Typically, an erection is caused by the increase of blood flowing in the part of the cheap cialis called the Corpora Cavernosa, otherwise known as the erectile tissues. When the cheap cialis is stimulated, penile arteries are expanded to allow for greater blood flow traveling into the penis, whereas the blood flow leaving the penis is reduced by the contraction of penile veins. This results in a healthy penile erection. The more blood that the erectile tissues hold, the harder the erection becomes.

As we age, it is common for us to notice a drastic change in our penis size and erection quality. While this used to be highly embarrassing and many men kept this fact hidden, the world is a changing place and today, the understanding of how the penis works is much more comprehensive than in years past. Both prescription drugs and herbal supplements have been introduced to the market, assisting men in achieving both stamina and penis enlargement.

While some men choose to try prescription medications first, they are learning that these medicines are not all that they are toted to be and do not always result in the penis enlargement that one had hoped for. In fact, the side effects caused by these medications can be quite unnerving! More and more men are turning to herbal remedies because they are natural, they work better, and they do not have the side effects that have been associated with their prescription, synthetic counterparts.

MacaEnhancer is the most popular of these supplements. Other popular supplements include Vig-Rx, Maxaman, and Virility Pills, to name just a few. There are websites on the Internet that will allow you to compare the differences between the herbal supplements and what you can expect them to do for you. All are natural substances with some, like MacaEnhancer, utilizing ancient herbs known throughout the ages to assist in penis enlargement. These supplements have been proven to increase sexual stamina, plus heighten desire, as well as show a marked growth in sperm count.

About The Author

Dr. Michael Rodriguez is an innovator who has spent the past decade researching male sexual health.

Penis Enlargement

DXN Roselle Tablet ( Natural Vitamin C )

DXN Roselle Tablet ( Natural Vitamin C )

Roselle Tablet (Natural Vitamin C)

Roselle or its scientific name Hibiscus sabdariffa is a wonderful flowering plant growing in both tropical and subtropical regions. The swollen red calyces of the plant contain abundant amount of vitamin C and minerals such as zinc, calcium and magnesium.

Now, with DXN Roselle tablet, you can grab the natural goodness of Roselle in a convenient way. The exclusive DXN Roselle tablet provides sufficient vitamin C, D, B1 and B2. You will benefit from a wide range of nutrients while enjoying its fabulous taste.

When it comes to vitamin sources, nothing could beat the natural. That’s just what Roselle Vitamin C has to offer- 100% natural vitamin C to help strengthen your body resistance against diseases, promote healthy gum and beautify your skin complexion.
No preservatives, artificial coloring, and flavoring. It is approximately 6x more potent than lemon.

For general well being:

Children (1 year – 12 years): Take 1-3 order cialis daily
Others: Take 3-6 cialis daily