CML- Early Diagnosis & Excellent Results in Era of TKI

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CML- Early Diagnosis & Excellent Results in Era of TKI

3 Aug, 3:30 PM

Transcript [Music] good evening everyone i'm dr niveda and i welcome you all on behalf of team netflix so this evening we have with us dr charaksha who is an md medical oncology and hematology from the usa he is currently a consulting hemato oncologist with the polo hospitals and with nearly two decades of experience areas of interest lions stem cell bone marrow transplant uh hematology uh breast cancer head neck gastrointestinal liver lung and other cancers as well along with that so has a number of publications to his name um really lucky to have you with us tonight on netflix and we'll get started with uh your discussion namaste and thank you vegeta for that introduction and netflix today's topic is chronic myeloid leukemia a very important topic because cml is one of the uh poster child of the targeted therapy the first real targeted therapy in the field of oncology hematology came in cml and changed the survival the prognosis completely so let's see today we'll talk about cml main aspects that is one it is one of the best uh curative cancers or one of the best survivals in cml how to make an early diagnosis how to monitor the treatment for response and the role of tyrosine kinase inhibitors the targeted therapies and functional cure we will be using the cml tree that you are seeing here which um at multiple times to understand the how the diagnosis is made the pathophysiology monitoring and treatment so first of all the molecular genetics of cml we are all aware of this that this was identified about three decades ago that bcr and abel join to make a bcr able protein and these are derived from chromosome 9 and 22 and this vcr able protein turns on the cell proliferation continuously so that leads to accumulation of more and more cells and that is how we see the cml patients with high white cell count and many times with high platelet count as well now why cml is important why we are discussing this topic for this one slide if you can remember that is the most important message of today's talk that cml now treated well has survival same as general population for those who achieve complete cytogenetic response within two years of starting imatinib so this is very important that a cancer which when i was in medical college about 25 years ago 30 years ago the median survival was about two three years and many of you may remember these were the patients in the exams uh practical exam with large spleen so for the splenomegaly examination these were young patients and unfortunately they survived very short and now we are talking that their survival is same as general population this is something we can say for very few cancers today that having survival same as general population so we will talk about these other the parameters that define that success over the top now as you can see that imagine it how it changed the survival if you see the lowest graph the lower two graphs are with hydroxyurea and busulfan and that the the survival was very low and then with interferon alpha the next graph it improved a little bit then with stem cell transplant it reached somewhere in the middle here and now with imatinib alone it is here so this is the power of the tyrosine kinase inhibitor imatinib where the results are so much better than even transplant okay we got from transplant which is the kind of ultimate curative treatment in blood cancers what it could achieve and what imatinib is achieving is so much much better so that is why early diagnosis of this disease is very important because we can give a great prognosis survival to these people so how do these people present these are some of the examples from our practice 40 years old man with fatigue weight loss of about 5 kg over 3 months and on examination you find a spleen about 4 centimeter below the hostile margin and you do a workup basic work of cbc shows wbc of 70 000. emo will be normal and plated also 800 000 8 lakh high platelet a very classic presentation then there are other people who present slightly differently like this woman who came to us with only a high platelet count at 18 lakhs but with normal wbc and hemoglobin 12 she had a workup somewhere else with bone marrow blood workup molecular test that is jack ii and she was labeled as milo proliferative disorder essential thrombocytosis and she was started with hydroxyurea but she was not getting very good control of platelets so she came to us we did the workup and she was diagnosed with cml and that led to her appropriate treatment with tki and within one month her platelet count was normal and is maintained like that now for about two years this is an increasingly common scenario a young woman or a man going for pre-employment health checkup or routine blood workup find a slightly raised wbc it's near normal everything is normal patient is asymptomatic so they are called for a repeat cbc after one month by the physician again no change they are asked to follow up after six months wbc is slightly higher now 18 000 but the smear review is again normal and patient is completely asymptomatic working 10 hours a day so nobody is understanding what is going on they are referred to us and we do the test and the diagnosis is made so the typical presentations of cml are that now increasingly asymptomatic high wbc count uh whether it is done for routine health check or pre-employment or sometimes for some other thing like the patient going for a surgery hernia surgery or a cosmetic surgery anything else and they end up getting blood tests which shows high white cell count and they get diagnosed the typical presentation we all know is fatigue weight loss low grade fever early satiety because of a big spleen abdominal discomfort and on examination classical splenomegaly um a very odd uh presentation in some patients is reduced hearing so people who get wbco or five lakh seven lakh have reduced hearing and as their counts are improving with treatment their hearing improves this is very unusual finding atypical presentations is increasing platelet count only and if the platelet count is more than 10 15 lakh these patients may come with bleeding such as we had a patient with 30 lakh 32 lakh rather a platelet count who came on a sunday with significant bleeding from gums so in this patient we had to do emergency lowering of platelet count by platelet afferences to control the bleeding and by reducing the platelet to improve bleeding and these are the patients whom you should not be giving experience for high platelet count so actually this is acquired one belly brand disorder will not go into detail but important to remember that patients with extreme high weight a platelet count don't start aspirin another uncommon very uncommon presentation is only high eosinophil so eosinophilia more than five thousand ten thousand uh can occasionally be a presenting feature of cml the typical blur smear in cml is called as bone marrow in blood so you see all the different cells that you are supposed to see supposed to see in bone marrow are being seen in blood such as normoblast myelocytes metamylosite promyelocyte etc and however again remember that those occasional patients who present with minimal white cell count as part of routine checkup frequently have a normal blood smear so if normal blood smear but persist on wbc over six months you have to think of cml now what is the diagnostic test the based on the smear and history we have suspected but the diagnostic test is to find vcr able so this is the confirmatory test that protein which forms from the translocation of 9 and 22 chromosome pieces and what are the tests so initially we were doing bone marrow and based on morphology people said that okay this most likely cml but the diagnostic test is to find missile able translocation by karyotyping which was the oldest test but it has the sensitivity of finding about 1 in 50 cells at 1 in 50 abnormal cells then came fish analysis which is more sensitive so occasional cases which are missed by karyotyping are picked up by fish and pcr is a technique that detects between 1 lakh to 10 lakh one cell between one leg to 10 lakh in the bone marrow so most sensitive tests we use it more for monitoring rather than just the diagnosis although it is very good for diagnosis as well and what this tree is showing you that the what you are seeing above the surface is the white cell count and what you are seeing below the surface is the root cause of cml and the root cause is this genetic change and as you go lower and lower the pcr is the smallest root and our goal is ultimately to eliminate the smallest rules so that we get the best disease control now etiology of cml patients always ask but no one knows various theories but the only known established cause is high atomic radiation exposure as in hiroshima or nagasaki but in the routine life that we see today there is no identifiable cause what is the prognosis again survival is same as general population for those who achieve complete cytogenetic remission within two years of starting imatinib so important to remember that this is a disease we would like to diagnose early and we need your help in early diagnosis and timely treatment so that we can give these people the best survival so now we will talk about the medicines but very important from the point of view of non-hematologist oncologist is the fact that these are the factors affecting prognosis and where you can make a difference so the number one factor is compliance number two is compliance and number three is compliant so the idea is that i am highlighting the importance of taking very very regular medicine the studies are shown that if you miss even three to four tablets a month your pcr control rate goes down means your long term survival is compromised and this is where the your role is very important to continuously emphasize to the patient that they should not miss any tablet even if they have minor side effects such as acidity bloating little bit of edema there is a tendency to stop the drug worry about the long-term side effects short-term side effects somebody will come and say oh allopathy medicines are not good for this that if there is edema very common side effect is a little bit of very orbital edema and so in the morning when they see this edema or when the friends and family tell them oh you have something you have edema you look different people tend to get worried a lot of people associate edema under the eyes with kidney damage so they think that there is something happening with their kidney and they will stop and check please don't do that and i emphasize this at many visits initially many much more times and later on also especially when the reports are good because when the reports are good there is a tendency to again be complacent and it is okay you know now we have anyway achieved excellent remission so even if we forget sometimes it is okay that kind of tendency settles in the patient's mind so please please you you must advise your patients because after the initial care we call these patients every three to four months only and so that is only three times a year that means they are following up with you more times so they should not stop medicines out of fear with drug interactions without checking if there is a really need to stop temporarily if they are getting any antibiotics or any other inter current illness or they may have gastritis and they may stop so whatever different reasons they may think that you know it is okay to stop if they have a fever viral fever they'll stop for five days all medicines so please at those points make sure that they don't stop this medicine and by far with large majority of the drugs it is safe to continue tki especially if it is a self-limiting illness where you are going to give medicines only for about say five days or seven days then there is not even the need to worry about drug interactions other factors are various scoring systems all these scoring systems take into account mostly age splint size at diagnosis platelet-counted diagnosis and blast percent in peripheral blood very surprising and interesting fact is that the white cell count is not in any of the these prognostic scoring systems which is you know one of the interesting aspects of medicine that when you analyze large database you you sometimes find things which seems so simple logical that white cell must be a part of the scoring system but it is not and there are few other things like cytogenetic abnormalities other than pillar defect chromosome or bone marrow fibrosis at diagnosis so now coming to the treatment um what are the treatment options the older ones hydroxyurea or musulfan uh which as we have seen they work only uh very poorly and the if you remember the initial survival curves they are providing very low results then the interferon um i when i was in fellowship we were using interferon at that time even regulated interferon was not available so this was a very difficult treatment every day injections very few people could continue even with peg interferon a very long term is not easy um and the results are of course not as good as tki and then in 2001 during my third year of fellowship this data came out and it changed the landscape completely and the before imatinib across the world the number one transplant indication was chronic myeloid leukemia number one across the world in all the major transplant centers after imatinib now it is not even in top five so that's the power of imatinib that it has replaced allergenic transplant as the first treatment or even secondary so tki is the tyrosine kinase inhibitors is what we will be talking uh the how do we monitor before we go on how do we monitor these people with blood counts bone marrow cytogenetics and pcr again the improvement in the pcr technique has allowed us to stop doing bone marrow cytogenetics repeatedly because the pcr correlates so well with the prognosis and this is the point if you remember the complete cytogenetic response here which correlates with the pcr of less than one percent and if you remember if we can achieve even this complete cytogenetic response as we've seen earlier slides makes the survival as normal as general population whereas our drugs today go far below that so this this picture here is showing how we are able to now achieve pcr less than one percent then less than point one percent and in deeper molecular emissions we can achieve up to less than 0.003 percent which is known as the mr 4.5 molecular emission 4.5 that is the current best achievable measurable outcome so reminding again that if you achieve complete cytogenetic remission this survival is same as general population and this we've already discussed that complete cytogenetic remission correlates with a pcr of less than one percent so now what is our treatment goal now over these 20 years a lot of work has happened in the field of cml understanding the monitoring also how best to follow these people minimize the need for bone marrows and other work up and make their life very easy so current goal is to achieve at least mmr which is pcr less than 0.1 so pcr less than 1 is what we saw is a very good result already but we are aiming a little higher for the safer side that pcr less than 0.1 percent now we were very happy with this level of response which is known as mmr and when patients achieve this we we told them there is nothing more to achieve and just continue the drug and kind of be happy however at that point we were telling the patient that you have to take this lifelong and then came this data of tfr or potential cure which you will talk about and there the achieving the pcr even further below these smaller routes of the cma tree became more important because now if we are able to remove the smallest smallest roots of cml tree then we can even stop the drug in some patients so that is where we started measuring pcr more frequently the tki is available now 2001 it was only imatinib after about six seven years we had the satiny and nilotini then very recently uh in bosutini and last one year or so even estimate so now we have six different tki's what was the need to have all these tkis because we know that yes imatinib is wonderful very safe in most cases and you know great results survival but in the original study of irish study the 2001 publication we saw that about over the years about 40 percent of people for various reasons ended up needing to discontinue imatinib either because of progression or some kind of intolerance and because of that there was a need for these second generation tkis which are nilotinib desatinib and bosotini and then third generation tkis which is ponatinib and assymine and they overcome the resistance to imatinib in many cases we have now the ability to measure specific mutations so based on mutations we can decide that if somebody has progressed on imatinib and has say x mutation then we go to this drug why mutation we go to this term z we go to other drug like that so that kind of detailing is now possible which allows the survivor to get even better and better so now coming back to the cml tree uh why did hydroxyurea and musulfan did not improve survival because even though these drugs improve the wbc count to completely normal these two drugs can make your cbc absolutely normal and yet you don't get any improvement in survival because you are not doing anything anything to the root cause and the root is where these newer drugs work so imatinib was the first tki which worked on this route which we call the the karyotype the chromosomes where it achieved 80 percent cases it could achieve complete cytogenetic remission and the optimal goal which is mmr it could achieve in about 60 percent people and deep molecular emission which is a prerequisite for potential cure or stopping the drug in about 40 now the second generation tki here did better on all those parameters all the way up to deep molecular emission of 50 to 60 percent so that is the power of the second generation tkis now so how do we choose out of so many drugs do we start everybody on imatinib and then only if they have a problem we go to second generation tki no these studies have verified the role of these drugs as following that if you have a high risk or intermediate risk patient by so-called score one of the scoring systems that we saw earlier then you start directly with second generation tki because their survival is lower with imatinib as we see in the next slide if the patient has low risk social score then he or she has option of going to either the uh imatinib or the second generation tki why because this survival as of now is same with both imatinib or second generation tki in low risk but the deep molecular response the lowest roots clearance is better with second generation tki so imagine the young patient that we saw the 30 year old girl woman who at pre-employment health checkup had found cmn now imagine telling her that you have to take this drug for life long which means another 50 70 years of her life so for these patients stopping drug has a huge value if they can achieve deep molecular response and that is why so if the patient is younger and places more importance on stopping the drug then you start with second generation tki you don't wait for the first generation response the what i mentioned earlier that the survival at 10 years in the original study of imatinib in the low so-called score patient is almost almost 90 percent in intermediate it is about 80 and high risk it is about 70 so 70 80 90. so for the low risk patients clearly there is not much value unless you are thinking of stopping the drug now so uh these studies then evolve the criteria as to when to start thinking about changing the drug if you have started somebody on immaterial and this is like we follow the pcr at every three months initially until we achieve the optimum results as you can see here that in the first the green one the green here is optimum so that means pcr should go below 10 percent at 3 months below one percent at six months and below 12 months at uh below 0.1 percent at 12 months if this is not happened then they are either in the warning area or in the red area depending on the level so say for example if at 12 months bcr is 0.121 percent then you could still wait this is a warning so means you follow them more regularly but you don't have to change the drug and but if it is more than one percent at 12 months then it is a failure and that means you have to change the trunk so that is we are not going in the detail of all time points but this is an important understanding that how we are now able to predict well in advance as to which patient needs a change of drug now it is uh important to understand that as of now the second generation tki at first line treatment from starting have not shown any improvement in head to head comparison against imatinib showing any improvement in overall survival or pfs progression free survival so as of now because of this reason imatinib is still a reasonable drug to use so if you are patient with multiple comorbidities cost issues you can still use imagining only and you don't have to go to second line tki from start however as i say it is more important for people who are thinking of pfr stopping the drug so the benefits of second generation tki as of today is mainly in the front line is to achieve a more rapid response and potentially develop fewer mutations because of quicker response and less slightly less incidence with nilotinib of progression to cml second or third phase that is accelerated or blast crisis now again showing this data of uh these various drugs giving these the second line tki is you can see here giving better uh the deeper molecular response that is uh if you compare in the the certain trials 33 versus 42 percent in nelotiny again 30 versus 50 percent so the deep molecular response is higher as we had seen earlier in the cml tree also now a brief uh comment on the adverse effects of these medicines a lot of them are mentioned here but the discontinuation rate due to adverse events of is extremely uncommon very occasional people develop severe rash just like drug allergy that can happen with any drug very occasionally lot of edema and then we have to stop and sometimes too much gastritis that people cannot handle but that is rarely a cause for discontinuation similarly um with dasatinib and nilotini now this study is showing starting with a lower dose and getting the good control achieved even with lower dose has reduced the side effect rate um and allowed to continue drugging most of the people safely such as in the certainty lower dose of 50 milligram has shown excellent results and at least in the study so far the discontinuation rate is extremely low the most common ones that i mentioned earlier gastritis so we advise them to take the drug after a meal or at least after a big glass of water preferably after breakfast or lunch avoid after dinner or late at night when the gastritis incidence will be higher um the one of the side effects uh which is you know some people could say even a pleasant side effect uh or so is that there is a kind of knee pigmentation so people become fairer and it is very noticeable within few weeks to months that the person becomes more fair although some people become too white and they complain that the relatives are asking what has happened to you you look very pale and etc some people develop some pigmentation over the cheeks which is a bit annoying to them is you know when people are asking and the baggy eyelids here the edema so these are the complaints of most people because you know this is a lifelong treatment and people notice and ask about these things certain specific side effects to the satiny is effusions plural or pericardial effusions and pulmonary arterial hypertension on a summer short term some are long-term side effects neurotinib also somewhat increase cardiovascular events in the very long term and in the short term pancreatic pancreatitis high glucose and indirect hyperbilirubinemia cutie prolongation ponatinin is fortunately used very uncommonly and is a difficult drug where the risk of thrombosis is high at the standard levels but there are now studies of lower dose showing matter safety and still good results bosutinib is more of gi side effect like diarrhea so now last few points the treatment free remission in cml as we spoke about that the the biggest attraction now is that we are able to stop treatment i have about 12 patients who have been now off treatment of cml for many years uh one of them a very young man about 25 28 when i think we started and he was able to get off the drug after about seven years and that helped getting married for him because can you imagine for a young person having a label of a lifelong disease and continuing treatment so avoiding side effects that impair quality of life especially in younger patients is the number one reason for stopping tki some people have side effects which require stopping also we don't know the very long term side effect of these drugs although so far it is fairly safe but not completely safe and we understand that the data is only about 20 25 years old so when we are talking about lifelong means 50 years 40 years and even children so imagine a 20 year old who starts today and has to take life long okay so for them this is very important another very important point is family planning and pregnancy so for young people that's a very big consideration that if you are pregnant you cannot take this drug and that means uh it creates a big dilemma for them one side they have to worry about the disease control other side they are losing the age of getting pregnancy and they want to complete child bearing so this is a very important discussion point in our practice with young patients what to do how long to wait what are the options to use uh etc and so family planning is one important financial reasons we are talking about lifelong treatment so the cost becomes important although i must mention now that luckily the cost of tki's because of generic versions is very low now and imatinib good company's imatinib is available at about 1500 rupees per month which used to be 200 000 2 lakh rupees a month when the drug came out and it came down to twenty thousand thirty thousand ten thousand and now it's less than two thousand rupees a month now although discontinuing tki seems very exciting but there are certain important criteria because we still don't know how many people in the long run will have a relapse of cms uh initially when we stop within those who are likely to relapse do so within generally first one or two years and that to mostly six months what has happened in my patients also that for six months only they will have a pcr coming back from negative to positive and uh but i had a patient who converted to positive after seven years of being afraid so since we don't know which patients will actually be truly truly cured we call this treatment free remission or a functional cure rather than real cure and that is why a very regular monitoring is important so when we choose a patient for discontinuation we make sure that they understand the need for lifelong monitoring and repeated pcr pcr is a bit costly test so they have to understand that they have to do every two months this test uh for one or two years and then at little lesser frequency every three months for uh at least for life long as we know now and over the years we'll know some more details also there are some criterias i will not go in all the details but briefly the patient has to have a they has to be on the drug for at least five to seven years and at least last two years the patient has to be deep molecular emission that means the what we discuss less than 0.01 or less than 0.003 at least that level they have to be continuous two years so the patient has to be very complement also and be able to get reliable repeated pcr uh then only this discontinuation can be considered and this is uh clearly um so this is not a futuristic thing stopping drug is possible as i said i myself have 12 patients at least and there are more than 50 publications on drug discontinuation with more than 2000 patients in these studies who have been able to discontinue so it is possible and there again your role is important that if you are following up with your patients about this and telling them to ensure that the compliance compliance compliance then they will achieve this good results in the long term and your nudge at every clinic visit to tell them that it is important your small reminders will be very useful to them and you provide them support and help that if they are worried about the cost then you can refer them to some ngo you can let us know if they are worried about side effect you can let us know uh if they're worried about child planning again we can counsel them if they have gastritis you can treat them but those should not be the reasons to stop in between let go drugs so that when the all doctor community will understand the importance of compliance we will be having these great results and will be able to even discontinue the drug in more number of patients the this slide is showing that the study is done of discontinuation with imatinib where it has been possible in about 30 to 60 patients with uh the second generation tki we have achieved that in about 41 to 63 67 so almost same slightly higher you can say with second generation tki and definitely faster with second generation tki so for younger patients many times that faster is also important they are in the age of getting married or in the age of getting children and they want to get off the drug very quickly too so in summary my last slide cml early diagnosis is very easy if it is suspected so it is important to remember even in atypical presentations like very high platelet alone very high eosinophils alone or routine health checkup no symptoms high high wbc but persist you don't want to start testing people are thinking about cancer in the first one or two months of high wbc but if six months continuous if there is high wbc then this should be considered overall survival is now same as for general population in at least 80 percent of cml patients treatment is easy overall once or twice a day generally very well tolerated it is not expensive and there are many government schemes ngos which provide these medicines so no one should be left without pki treatment in the first line at least and close monitoring with pcr is important not to get happy with just cbc uh coming normal which also is an issue many people feel good in pc completely normal all the time desktop monitoring coming to us they don't get pcr check and then they miss all the warning signs on the pcr and the routes from the we lose the control from smallest route to this level this and then they come here in blast crisis or full-blown accelerated phase and then the cure rates especially after blast crisis are very poor functional cure or treatment free remission is now possible in about 50 percent of patients and for those who fail first planet options are available at and ultimately hemetropoetic stem cell transplant or bmp is still an option for some patients about 10 patients or so will still need the transplant thank you thank you sir for that wonderful presentation uh you can start putting in your questions in the comment box or you can also use the raven feature to come up on stage in our discussion with sir uh so we start taking a few questions that have already come in uh we have dr nissar was asked uh can child planning be done with a patient on tki excellent question yes child planning can be done but in the first trimester the tki has to be stopped with second and third trimester the knowledge is not very very clear because it also depends on which tki the patient is on then also if the patient is achieved deep molecular emission we can even stop the drug and these things require a lot of discussion of the pros and cons because on one side there is a concern of losing disease control and the other side is child planning but yes in general the child planning can be done while the patient is on tki and as soon as they miss the first period then you stop the tki so in the first trimester you are not on the drug thank you sir also we have another question by doctor uh can we shift to first gen from second gen when pcr goal is achieved and when to change drug only for side effect from a side effect point of view very good question shifting from second back to first generation no studies to show that and if the pcr goal is achieved then we assume that that goal is achieved by that second generation pki so you would ideally want to continue that to maintain that goal because going to first generation you might lose that and when to change the drug only for side effect point of view um there are certain side effects uh which you know a grade three or four for example if somebody has a serious plural effusions uh leading to uh major respiratory difficulty or hormonal edema we have had occasional patients i can i remember at least two patients where i had to stop because of that in my 20 years of practice so it happens but those are very uncommon um some people get very severe milo suppression their accounts just stay low we stop hold restart at lower dose still they cannot you keep on changing occasionally rashes of course like any drug allergy so those are the points where we have to change [Music] so the good thing is that i mean incorrect diagnosis now of missing cml happens but wrong diagnosis of cml is now very very rare because the testing is so good detection of bcr protein is now extremely accurate and false positive is very rare so you know and if this is not cml and if you give imatinib you will also know in one or two months because it will not work so you will not get control of the by itself the patient develops side effects on first-gen pkis when to start second or third gen or generation dpi right so like i as i mentioned some of the side effects and then there are grades so people would if somebody develops mild purely fusion we would not change the drug or if somebody develops mild low cbc mild to moderate we will not change the drug but if it is very severe then we will change the drug so every side effect we grade them as kind of grade one two three and four so for a grade four we certainly change grade three plus minus uh and grade one or two we generally manage with those reductions thank you sir we have dr pooja nagpal actually he was written a question but uh dr pujam sorry i'm not able to read the question properly if you don't mind you can use the raised hand feature and come up on stage i'm only able to understand is this drug effective in a broad the the comment is not coming properly so if you don't mind could you please uh retype that or you can use the raise hand to come up one state yes you can see now is this dog effective in bcr abl negative cml uh not effective and now we don't use the word miserable negative cml earlier you know this term was used but not any longer so those are not cml practically and the drug does not work another question how the effect is monitored so um as we have discussed the monitoring most commonly done with the pcr although initially it is cbc and in 90 plus patients cbc will become normal within one month which call it complete hematologic remission that is achieved in just one month regardless of the initial white cell count then after three months we do pcr and then we follow it every three months some people do a bone marrow with cytogenetics at one year although we don't do it and most people don't because for patients it is very uh you know inconvenient and a bit painful also um dr krishna who's asked if there are any risk factors for other family members uh in cma so um the no known risk factors for practically all the blood cancers cml aml all cll chronicling for leukemia none of these have known risk factors like we say about say breast cancer or head and neck cancers like that uh will tki still work so in the accelerated phase the tki will still work now in that phase we have to do the mutation check first because certain mutations will make the cml resistant to the standard drugs so that means like we discussed earlier that if there is x mutation you give this drug y mutation you give that drug say for example if t 131 i mutation then only ponatinib or assiminib will work nothing else will work so none of the second generation tki will work so there it becomes very important to do the mutation testing which is again widely available in india now blast phase the drug will work but temporary and in large majority of the cases it will be few months and occasionally longer so it's not zero zero but it is uh nothing compared to what we're talking in the other phases so that is why in blast phase important to refer the patient for transplant and seriously consider transplant and monitor their pcr very close you don't get happy with this cbc control so if their pcr is not doing well then you know that they have to go into transplant otherwise if they are reluctant if they are older sicker other reasons then you may kind of you know continue monitoring with pcr and there are patients who do well on tki uh even after blast crisis but it is a smaller number so we have to balance in all the other factors uh thank you so much i think we've covered all the questions that came in um if we just wait for a couple of seconds more if there are any more questions uh please put them into your comment box and we will uh them so we have doctor porous who's asked what to do if there is milo suppression right so depending on the grade we would either continue reduce the dose or completely hold three levels now in general at least in the initial phase we really want to avoid stopping the drug this is a very important question thank you for asking that because this happens in the first few months very commonly that people who would have a marrow clearance of the bad cells and then actually from say 70 000 wbc they will go down to 3000 or 2000 so people get worried they stop the drug hold it for few days these that allow it to come up and that really reduces the long term control and all the goals that we spoke about of achieving good pcr control at three months six month one one year all that you you lose out on that heavily so for uh say grade 2 1 or even grade 3 we would actually push at that time in the first few months with growth factor support etc because most of these will actually recover back to good level where we can continue the same there are some people who even after the first month two months continue to have trouble and they are the ones where we have to reduce the dose and occasionally we just cannot continue unfortunately you change the tki we do different different things but in general we push through the milo separation without stopping the drug very important um think we are at the end of the q a um thank you so much sir for coming on to netflix and we look forward to having you for more future sessions on netflix as well um we do have a session request uh please take a session to differentiate different blood cell disorders so thank you dr nassar we'll stay in touch with sir and we'll plan these sessions with him uh as for his convenience thank you sir wonderful session and i'm sure our audience has taken a lot of knowledge back with them into their practice um thank you so much thank you netflix thank you dr nivedita and all the listeners and those who ask all the questions


Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. It was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. Tyrosine kinase inhibitors (TKIs) have successfully altered the clinical course of CML and continue to be a flagship for molecularly targeted therapy. Some patients, meanwhile, show primary or secondary resistance to such treatment and require an alternative course of treatment. As a result, evaluation of early response to TKI treatment has emerged as a crucial technique in the clinical monitoring of CML patients. Join us live on Medlfix as Dr. Chirag Shah explains how therapy with TKI for CML has evolved over the years.


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