ASH2011 - Two New Winners for CML by Dr. Cortes
Posted 27 December 2011 - 07:28 AM
Thanks for sharing this!
Ou plutôt merci pour le lien (Je tente en français )
Posted 27 December 2011 - 01:19 PM
Thanks for sharing, but I was not able to open the link, what does it say????
Posted 27 December 2011 - 01:49 PM
Hi Dina, Actually you have to create an account to see the video. It is doctor Cortes speaking about bosutinib and dasatinib. They put the text below so here is a copy :
Hello. My name is Jorge Cortes. I am the Chair of the Chronic Myeloid Leukemia (CML) Section and Deputy Chair of the Department of Leukemia, Division of Cancer Medicine, at the University of Texas, MD Anderson Cancer Center in Houston, Texas. Welcome to this edition of Medscape Oncology Insights on Chronic Myeloid Leukemia.
Today, I would like to report some of the significant studies in CML presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) being held in San Diego, California.
The Tyrosine Kinase Inhibitor Pipeline
There are 2 new drugs that I would like to discuss today. Important studies have been done on these drugs, which offer new treatment options for patients with CML in specific scenarios. The first drug is bosutinib. Bosutinib, like dasatinib, is a drug that inhibits Abl and Src tyrosine kinases. In contrast to all of the other tyrosine kinase inhibitors that we have, bosutinib does not inhibit c-kit and the PDGF receptor. So initially, studies looked at using bosutinib as second-line therapy, which led to a study using bosutinib as front-line therapy in CML.
Let me briefly review what has been presented at this meeting. In terms of the second-line use of bosutinib in patients in whom imatinib therapy has already failed and as third-line therapy in patients in whom imatinib therapy and therapy with 1 or 2 of the other tyrosine kinase inhibitors has failed, additional data were presented showing how the mutation profile of patients at the time of prior therapy failure can be predictive of patient response to the next tyrosine kinase inhibitor. Bosutinib has a good profile. It inhibits most of the mutations that we see in the clinic. The obvious exception is T359 and another mutation, V299L. The response is good in all of the mutations that are present in patients whose prior therapy failed and this correlates with major cytogenic responses and complete cytogenetic responses. The overall rate for the total population is approximately 50% of patients with major cytogenetic response and approximately 40% of patients with a complete cytogenetic response. Some of the subsets are very small, but you see responses in all of these different mutations.
In patients in whom bosutinib therapy failed, 2 different mutations were detected at the end of treatment, and these were T359 and V299L. What we learn from this -- and this applies to all tyrosine inhibitors that are being used for second-generation therapy -- is that detection of mutations is predictive of the response and mutations that are not very sensitive to a specific inhibitor may develop during therapy with that inhibitor. That means that we need to monitor our patients closely and when we are changing therapy, we need to look for mutations.
Bosutinib Up Front
The other important study is the use of bosutinib as initial therapy for CML. This was the BELA trial, which was a randomized trial of patients with newly diagnosed disease within 6 months of diagnosis. These patients were randomly assigned to receive either bosutinib or imatinib. The study was very interesting because the primary endpoint was the achievement of compete cytogenetic response at 12 months and the primary endpoint was not met. However, what we saw today were the results of treatment after all patients had been followed for at least 24 months. Major molecular response rate was significantly higher, and more importantly, the rates of transformations, treatment failures, and deaths were all significantly lower. Everything pointed toward a benefit with bosutinib even when the primary endpoint was not met.
Part of the reason that the primary endpoint was not met was toxicity, most commonly diarrhea, although most of it was grade 1 or grade 2. Therefore, many patients were taken off therapy very early in the course of this study and they were not assessed for a cryptogenic response.
In summary, the results are favorable. The patients had better responses and a better rate of transformation, and that is ultimately what we want, that the patients do not transform to an accelerated phase or blast phase. We don't want them to die, of course, so it is a useful drug both in salvage as second-line, as third-line, and certainly as front-line [treatment]. These studies are being evaluated now by regulatory authorities and hopefully there will be new treatment options for these patients.
Ponatinib: Impressive Results
Ponatinib is another important new drug. It is another tyrosine kinase inhibitor, but the important thing about this inhibitor is that, from the preclinical point of view, this drug inhibits the mutation T359. Furthermore, in studies in the laboratory, where you can essentially force leukemia cells to develop resistance to tyrosine kinase inhibitors, the emergence of resistant clones to ponatinib has not been demonstrated; whereas, you can make these resistant clones emerge to dasatinib and erlotinib and even more so to imatinib. That makes it a very attractive option, which has led to the use of ponatinib in phase 1 and phase 2 studies in patients in whom prior therapy with dasatinib or nilotinib has failed.
The results of the phase 2 study called the PACE trial were presented for the very first time at this meeting. These results are very early; the median follow-up was less than 6 months. That means that most patients had been evaluated only once for a cytogenetic response, but the responses are actually quite impressive -- 47% of patients in chronic phase achieved a major cytogenetic response, and most of these responses (nearly 40%) were actually complete cytogenetic responses. At this early stage in the treatment, those are very impressive results.
The responses are a little bit higher in patients who have the mutation T359 than in patients who had other mutations or fewer mutations. Everybody responded well; the differences were small. Ponatinib works in patients with or without a mutation, in patients with a T359 or a different mutation, and in patients who have more advanced stages of the disease (accelerated phase, blast phase). Of course, as you can imagine, in [patients with] more advanced stages of disease, the responses tend to not be as durable. Ponatinib is still an important component because two thirds of these patients had received 3 tyrosine kinase inhibitors or more. That makes it a very powerful drug. Of great importance, ponatinib was very well tolerated, there were no major problems with toxicities (some rashes, some dry skin, very occasionally pancreatitis), [but it was] a very clean drug in terms of safety.
Obviously, these results are early, we need to see them mature and we need to see what happens with longer follow-up, but ponatinib is lining up as a very powerful new drug in the management of patients with CML. At this moment, for patients in whom therapy with dasatinib or nilotinib has failed, where do we take it now? Time will tell. We need studies to see whether it can be moved up to second-line or to first-line, but it has a lot of potential.
The Drugs Keep Coming
It is a very exciting time in CML. We don't seem to be reaching an end to the development of one drug after another. The next one coming is better than the previous one, and this is great news for patients with CML. Evidently, it is critical that we identify patients well. We need to monitor them very closely and use our treatment strategies properly, but we are getting much closer to allowing patients with CML to essentially live a normal life expectancy and not die from this disease.
Thank you very much for joining me in this edition of Medscape Oncology Insights. This is Jorge Cortes reporting from ASH 2011 in San Diego, California. Thank you.
Posted 27 December 2011 - 02:22 PM
Thanks for posting this. I'm curious as to T359 and V299L. I assume that T359=T315i, though I'm not sure why there's a difference in terminology. I guess V299L has been around, I've just never heard of it though
All in all this is great news!
Posted 27 December 2011 - 02:45 PM
Thanks for posting this. I'm hopeful we will have better and better drugs with less side effects as quality of life is an important issue. The 1st and 2nd generation drugs have so many side effects, I find it very depressing. I think, sometimes, oncs. don't address the quality of life issue enough.
Posted 27 December 2011 - 03:47 PM
You got that right! > I think, sometimes, oncs. don't address the quality of life issue enough.<< I remember doctor kept saying (when I was DX in 2005) aren't you lucky this great new drug Gleevec. Then you take the drugs and go thru H.... you try to tell the doctors and they blow you off, like you are depressed and well "we can't blame everything on Gleevec" Then when my Onc recently said less change to a newer drug it will be a piece of cake. I said yea I know Dr... Only took me a year sick on Gleevec, she put her head down. I don't think they report half the stuff. Now that I am comfortable with the drug and she wants me to change without even thinking I would be do my homework before venturing out to change drugs because of PCR labs sent out of state that are questionable to say the least. Not only that but who says you have to have a deep response to live with CML. Yea I'm sure the less leukemia cell the better, but we still don't know long term effects on individuals, that takes years. Like you said Judy they don't address that quality of life.
Gleevec still may not be a piece of cake but I'm not complaining, not changing drugs and going thru who know what unless I really believe it as an absolute last resort. Beside Gleevec will become generic in 2005 lot cheaper if I lose my insurance. I don't want to depend on the charity on whether or not I met the guidelines of the drug company if I don't have to, I don't want to go thru that.
It is pure frustration, to think all my life worked 32 years, play by the rules and now I have to depend on the generosity of the insurance, which goes up and up and up after you retire. Jump thru hoops of the doctors, hospitals and insurance billing. Bad enough to have cancer and deal with all the phone calls and paper work, until your life becomes about cancer.
One doctor an Oncologist of 30 years + said in the old days we were taught to hit them hard and fast, until we actually killed the patient of the chemo instead of the cancer killing the patient. Now you will hear the leading experts say we hope the patient will die of something else before the cancer. Well just how do you know in the long run what these drug cause.
Don't get me wrong I be on gleevec for 6 years and I am still alive, I just really and truly don't think that science always reports it or tell it like it is!!
Posted 27 December 2011 - 04:16 PM
Hi Pam South. I started on Gleevec 200mg and felt fine with that but it wasn't working on a molecular level so I went to 300mg. At 300 mg I developed seborrhea, nausea, dizziness, increased fluid retention and rheumatologic symptoms. I switched to Tasigna and developed such a bad rash that my chin and the area between my eyebrows were swollen. I'm about to start Sprycel, I will start this after I see my new onc. (which is tomorrow). Yes, it's great that we have medicine that keeps us alive but the medicines can be very hard to take and most likely we will have to take them for the rest of our lives. It is hard having a chronic cancer, it's not exactly like having a hangnail. I value the quality of my life more than the quantity. I just hope I have a good result from Sprycel, both in terms of how it works and the side effects. I truly wish more oncs would address the quality of life issue. Just venting.
Posted 27 December 2011 - 04:37 PM
I would have done the same thing as you Judy.
200 mg of Gleevec did nothing for me, 400mg still cause some problems, 300mg is a good dose but it doesn't bring quit the response the doctor would like. But I say hey if it is stable and you are doing good. I told the doctors a long time ago when they wanted to push me on to the new trial 800 mg, NO, NO, NO. They just about drove me nuts. I'm thinking are they crazy. The doctor would say you will have no more side effects on 800mg then you do on 400mg, well if they fibed about the 400mg why would I believe them about taking double doses. I'm just not as trusting I naive as when I was younger.
Gleevec was not all that friendly the doctors made it out to be, but that was all that was out at the time. Tasigna & Sprycel came out later and by then I had become use to the Gleevec. It just sends shivers thru me to think of going thru that again on another drug. I went thru to much getting use to Gleevec to switch now.
I'm excited to hear how things go for you. As I never know if I have to change drugs what to expect, I guess different strokes for different folks,
Posted 27 December 2011 - 05:18 PM
I really hope you will tolerate well sprycel, I think this drug is better than gleevec regarding side effects, I personally do very well with dasatinib (plus as it is very efficient you can easily reduce the dosage if you develop some side effects, some people here are even treated with 20mg once a day).
Good luck with it !
Posted 27 December 2011 - 06:18 PM
Thank you Pierre for coping this news, any positive news out there are always welcomed!
Posted 27 December 2011 - 06:19 PM
Thanks Tiouki and Pam South. I really appreciate the support as I am depressed and nervous about starting a new med. and switching oncs. I always feel better after people respond to me on this board with great info and kindness. Thanks again.
Posted 27 December 2011 - 07:34 PM
Regarding what Dr Cortes said about looking for mutations after the first drug failure (which I whole-heartedly agree), I wonder why oncs just don't look up front to see if any mutations exist. Wouldn't that help in determining the course of treatment for a patient? But if I understand correctly, it appears that scientists are still unclear if mutations are present in the beginning or develop over the course of treatment (over time). Is there any study out there that discusses why it is not the standard protocol to look for mutations up front (or even every six months--whatever)? It seems that if it can be supported that some mutations are present upon dx or before a drug failure, it would be a waste of time to keep throwing TKIs at the CML until one sticks. Things may snowball out of control going that route when disease progression could be nipped in the bud. I hate to think this is just "old practice" and physicians have become complacent about the 5 year success rate of Gleevec at almost 90%. Clearly, one-size does not fit all and some of us do not have "time" on our hands no matter how "chronic" this disease is considered to be. For some of us, it moves rather quickly to the next stage. Anyone have any more or current info. or thoughts?
Posted 27 December 2011 - 07:43 PM
The reference to T359 should have been T315i. This is apparently a voice transcription software problem (along with Dr Cortes' accent) that did not understand the number sequence as it was said.
Posted 27 December 2011 - 07:56 PM
REGARDING YOUR POST >> I wonder why oncs just don't look up front to see if any mutations exist.<<
I have wondered the same thing. When I see my new Onc in January I am going to ask.
I would have thought I would have questioned this before as I was diagnosed in 2005 with CML.
Been on Gleevec for 6 years, Doctor had been on me for the last year to change me to Tasigna. I went to another doctor, for a second opinion, the new onc, is with a group of CML (leukemia) experts. I like to refer to them as the think tank. They to their labs in house so the labs should be much more accurate, as my labs were sent from my home town in Indiana to a lab in New Jersey.
I had never thought about that question until I recently came to this board to see how others were doing on their drugs. Then when I started reading about the different drugs being designed for certain location mutations. That got me to thinking? Hum.... wouldn't it be necessary to do a BMB to really know the mutation or can they simply tell the exact mutation from a PCR?? I wouldn't think a PCR would tell them as much as what is going on in the bone marrow where the bad stem cells is produced and mutations acurr on a higher level then at the bottom level of PH+. But then I am bit confused as the original mutation starts somewhere at the top of the stem cell before it even makes the blood. Then you have the mutations on the level of the PH+ Chromosone #9 & Chromosome #22.
However now that I have given it some more thought the experts must be talking about the mutation at the PH+ #9 and #22 level because the TKI drugs do not kill the ancient mother stem cells only the PH+
Perhaps Trey could answer that?
Trey, Could you give us some insight as to the mutation that occurs at the ancient stem cell mother that creates this whole mess of leukemia vs the mutations at the bottom level of PH+? When the expert talk about the mutations regarding which drug works best are they talking about mutation on the ancient stem cell that creates the leukemia or on the bottom level of mutation for the PH+
Posted 27 December 2011 - 08:01 PM
Hi Tedsey or anyone else out there. If a person has a mutation would a medicine still work on a hematalogic level but not on a molecular level or would it not work at all? Also, can a mutation test be added on to an old specimen, say one week old, or does it have to be done on fresh blood? Does anyone know? Thanks.
Posted 27 December 2011 - 10:23 PM
The issue of doing a kinase mutation test at diagnosis has been discussed. But kinase mutations do not normally show up early on. They tend to show up over the first couple years after diagnosis. This is believed due to the TKI drugs killing off the non-mutated cells, then the mutated ones are the ones that remain and multiply. The mutated cells are not normally detectable until they multiply for a while.
There has been some confusion expressed about mutations. There are two main types, and they are very different. There is the chromosome level mutation (actually a translocation) that is the t(9,22) swap that causes CML in the first place. Then there is the second type of mutation we are discussing here which is the kinase mutation, whereby the "parking spot" in the BCR/ABL (which is not a chromosome) where TKI drugs park to shut down the leukemic process mutates so that some TKI drugs cannot fit into the slot any more, so the drug will not work. This generally happens to Gleevec more than the other drugs. Tasigna and Sprycel can work for most kinase mutations after Gleevec stops working. The new drug Ponatinib appears to work when even Tasigna and Sprycel fail.
Posted 28 December 2011 - 08:51 AM
The terminology refers to the specific amino acid mutation in the bcr-abl protein. T315i means that the threonine (T) in the 315th amino acid position in the native protein becomes an isoleucine (I) in the mutated version. The isoleucine has a big bulky group that prevents the drug from fitting in the binding pocket (lock and key must match). Similarly, V is valine in position 299 which gets substituted for leucine (L) in mutated protein.
Proteins are made up of separate amino acids strung together, and are often expressed as the sequence of aa's written out. The aa's are numbered starting from one end to the other so they can be distinguished from one another. So a protein might be written out as GGLVCAR, each letter representing a specific aa.
Come to think of it, the T could be threonine or tyrosine. Not sure I know the difference in the code well enough. On Wikipedia if you are interested.
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