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TKI Drug Response Rates


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#1 Trey

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Posted 17 September 2011 - 09:44 AM

One of the issues CML patients struggle with is whether they are responding well to TKI drug therapy, and ask "Am I responding quickly enough?"  It is normal to want a fast response, and some people do respond quickly to the TKI drugs.  But it is a continual theme that people think they should be responding faster than they are, since they assume most others are doing far better.  Let me put the issue into perspective, since there has been a tendency to overestimate the average speed of response to CML TKI drugs.

There is no one place to find the statistics, so I compiled them myself.  And since the stats vary by study, sometimes widely, some averaging and normalizing has been done to reflect an aggregated response rates among the various studies.  So these numbers will not line up with specific studies.

TKI Response Rates by Percentage (Compiled/averaged/normalized by Trey):

                                          400 Gleevec   800 Gleevec       Sprycel         Tasigna

CCyR by 12 mo                        66                  70                    77                    78

CCyR by 24 mo                        75                  80                    80                    85

MMR by 12 mo                         30                  45                    46                    55

MMR by 24 mo                         46                  65                    64                    70

MMR at 7 years                        83                  NA                   NA                    NA

PCRU at 12 months                   7                  10                    10                     11

PCRU at 24 months                 10                  17                    17                     25

PCRU at 5 years                      40                  NA                   NA                    NA

CCyR is a zero BMB or FISH.  MMR is a 3 log reduction by PCR.  PCR Undetectable (CMR) is a zero PCR or 4.5 log reduction on some studies.

As you can see, there are quite a few patients who do not achieve CCyR by 12 months, which is why the goal for CCyR is 18 months.  The MMR (3 log reduction) rate at 12 months is generally under 50%, which is why the MMR goal is about 2 years.  But you can see that a significant number do not achieve MMR by 2 years.  CMR/PCRU numbers at one year are generally only 10 - 20%, with the exception that Tasigna rates are higher (whether due to statistical anomalies or reality is yet to be seen), and the PCRU stats slowly rise over the years, although accurate data is not available.  Long term studies show that some patients have achieved PCRU in the 7 - 10 year timeframe after a long, slow, steady response.

The positive trend lines generally continue upward as years go by.  The biggest risk of drug resistance is in the first 24 months, after which the risk drops very significantly (although there are exceptions).

So it is important to have realistic near-term objectives for treatment to avoid disappointment, and to understand that an optimal response can take a long time.  The stats show that over the long term, the drugs provide for a deeper level of response, and a continual decline in the probability that the drugs might quit working.

These stats should also dispel assertions that Gleevec is somehow an "inferior" drug.  Response rates are somewhat lower for Gleevec up front, but Gleevec catches up fairly quickly.  So if Gleevec works for a person, then there is no reason to switch unless side effects are intolerable.  The main reason why patients switch from Gleevec are the side effects, not loss of response.

People respond differently to different TKI drugs, so the key is to find the one to which you respond well with tolerable side effects.  The best approach for doing this is trial and error.  There is no clear data to show which drug should be used from the start of treatment.  But early switching in the face of any significant loss of drug response is a very good idea.

This is dedicated to all you "slow responders" who believe you are in the minority.  If you look at the stats carefully, you will see that most of you are right on target.  And remember, these drugs have resulted in a 95% survival rate for CML.  Sometimes it is simply a matter of perspective.



#2 LivingWellWithCML

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Posted 17 September 2011 - 10:04 AM

Trey,

This is super helpful ... thanks for taking the time to "crunch the numbers".

For patients who start on Gleevec and end up making a switch - any idea what percentage make the switch due to loss of response vs. side effects intolerance?


Dan - Atlanta, GA

CML CP Diagnosed March 2011

Gleevec 400mg


#3 scuba

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Posted 17 September 2011 - 11:43 AM

Trey:

In your compilation research did you notice if the statistics separated out continual drug use versus patients who had to take drug breaks for one reason or another?


Diagnosed 11 May 2011 (100% FiSH, 155% PCR)

with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein

 

Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate

6-8 grams Curcumin C3 complex.

 

2015 PCR: < 0.01% (M.D. Anderson scale)

2016 PCR: < 0.01% (M.D. Anderson scale) 

March        2017 PCR:     0.01% (M.D. Anderson scale)

June          2017 PCR:     "undetected"

September 2017 PCR:     "undetected"


#4 Trey

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Posted 17 September 2011 - 01:19 PM

Dan,

Early Gleevec studies on a large group -- when there were no other available TKI drugs -- showed that 84% could remain on Gleevec and maintain CCyR for the 42 months the study lasted.  Now that there are more drug options,  patients will switch from Gleevec much more quickly due mainly to side effects issues, but also to attain a better response.  So given that early data when patients "had to" stay on Gleevec, the true resistance rate of Gleevec is something less than16%, with nearly all occuring within the first 2 years.  The issue of "intolerance" is an individual matter involving many side effects issues, so stats on switching from Gleevec due to the entire spectrum of intolerance issues is not generally known, although some guess it might be 30 - 35%.  Most of those would have remained on Gleevec if there were no other drug options.

Michael,

The stats include patients who took necessary drug breaks along the way during the studies.



#5 GerryL

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Posted 17 September 2011 - 06:23 PM

Hi Trey,

Since I'm still under the 24 months can I ask a question about whether there are any statistics about what the most likely stage people were at when the drug resistance showed up? I've got another 9 months to go to get to two years of taking Gleevec - next PCR test will be in October, then see the doc in November, but I'll run the figures past you if I can't work them out.

"The positive trend lines generally continue upward as years go by.  The biggest risk of drug resistance is in the first 24 months, after which the risk drops very significantly (although there are exceptions)."

I'm not expecting anything bad to happen (fingers crossed) just curious. My side effects are reasonably manageable - skin and fluid, so don't really want to swap drugs. I would like to get to PCRU so I could then talk to my doctor again in a couple of years about reducing the dosage. Hopefully there has been research done by then and he will be easier to convince about the idea.



#6 bull

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Posted 17 September 2011 - 07:52 PM

Trey , I very rarely post anything , but I am on here several times a day , and read every post. I just wanted to say THANK YOU , for everything you do and share. Keep up the good work !!!



#7 jjg

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Posted 17 September 2011 - 09:24 PM

Hey Trey, love your work! It is very useful data, don't suppose you thought of publishing a review paper. I don't know how hard it would be for somebody without an university/hospital/research centre affiliation to publish, snob factors aside it should be possible. Anyway I was wondering how you did the normalization and also if you know what the variances are for any of those numbers? Even if you just have a gut feeling for the variances - I imagine changes in population as the 2nd generation drugs provided additional options have skewed things a little.

For my own case we are lucky enough to be interested in the pointy end of the response data. I've had a 3.8 log response at 6 months with 600mg of gleevec which, while not quite as fast as yours is still at the pointy end. It is fortunate for us as I am 38, female, newly married and hoping to stop treatment to start a family and a fast response may make that possible. So S & T do on average give faster initial responses, but my question is are the fast responders to G as fast as the fast responders to S & T, ie. what is happening at the front of the response curves? My hematologist was like "good question" and I can see that it's difficult to know this unless you have the actual patient data rather than the averages that are published (often without the standard deviations). The PCRU @ 12 months does give some indication that for fast responders there is not much difference between drugs and in particular that the higher dose of G is similar to S & T. Would you agree with that?

I'm therefore wondering if I should be looking to move up from 600mg to 800mg (being in Australia the 2nd generation drugs are avaliable but not easily for somebody who is responding so well to G). My concentration levels at 600mg were only just above 1000 i.e. similar to average concentrations for those of 400mg. At 7 months I do have fatigue issues and other minor things but these are easing and my counts have just made it back into the bottom of the normal ranges. We are looking to get to PCRU as soon as possible and try for a pregnancy after holding that for a only a few months (I'll be 39 by then). Coming of treatment is scary so I want the response to be as deep as possible. Initially my hem was saying no to 800mg of G because she expected I'd end up needing drug breaks, but as my body has some experience with G now and we all get nervous about coming off treatment she might be receptive to trying a higher dose to push for a deeper response


Dx Dec 2010 @37

2x IVF egg collection

Glivec 600 & 800mg

PCRU March 2012

Unsuccessful pregnancy attempt - relapsed, 3 months interferon (intron A), bad side effects from interferon

Nilotinib 600mg Oct 2012

PCRU April 2013, 2 years MR4.5 mostly PCRU with a few blips

April 2015 stopped again for pregnancy attempt (donor egg), pregnant first transfer, 0.110 at 10wks, 2.1 at 14wks, 4.2 at 16wks, started interferon, slow dose increase to 25MIU per wk, at full dose PCR< 1 for remainder of pregnancy

Healthy baby girl Jan 2016, breastfed one month

Nilotinib 600mg Feb 2016

MMR May 2016

PCRU Feb 2017


#8 Trey

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Posted 18 September 2011 - 09:37 AM

Gerry,

Drug resistence most often occurs in those who "struggle" along with poor responses during the first couple years.  There are exceptions, but that is the norm.  Side effects are not a useful indicator that someone will lose response, so there are no "warning signs" except that a slow and poor response shows that the current drug could likely fail.  However, a good responder could become resistant, most likely from a kinase mutation which has been recessive and comes to the forefront over time.  So if a person is responding well to drug therapy, resistance would most likely come from a kinase mutation which has been recessive.  These kinase mutations are believed to primarily exist from the beginning of the disease, and it can take time for some of them to come to the forefront.  This is seen after the non-resistant CML is killed off, and the resistant form remains and increases, which is shown as loss of response.  In reality it is one form of BCR-ABL replacing the former as the dominant player.  So it can take some time for these kinase mutations to show themselves.  But after one year the liklihood that any will appear starts to fade away, and by roughly the 2 year point any resistant forms of BCR-ABL has likely had enough time to appear if it were ever going to appear.  There are exceptions, but the odds of resistance after roughly 2 years drops to a very low level (well under 1%).  So the 2 year point is not a magic thing -- it merely accounts for enough time for all forms of kinase mutations to appear if they ever will, although they would most likely appear within the first year.  After one year the probablity of kinase mutations drops considerably, so there is not a huge drop at 2 years, but rather a continually declining probability along the way.

The good news is that resistance to one drug does not imply  resistance to all drugs.  So the issue of resistance is not as worrisome  as it once was, since we can switch to 2 other drugs, or even to a  clinical trial drug.

See link below for a good discussion about the resistance issue:

http://onlinelibrary...011.01689.x/pdf



#9 Trey

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Posted 18 September 2011 - 02:40 PM

JJ,

I looked at a lot of different studies, and the data is all over the map.  As a result, I applied a fair amount of Kentucky Windage (KW)* when certain data did not line up well with data from other studies.  It might be called a poor man's Least Squares** approach with KW.  But don't tell PhilB or he will be all over my butt about how pure and beautiful True Maths can be when not in the hands of the unenlightened.  Anyway, I relied fairly heavily on the IRIS, DASISION, and ENESTnd data since they were large groups, but I did not simply used their data as printed, but rather made manipulations when other data conflicted.  So if something looked odd compared to other data it got manipulated.  My methods would not pass for a strict scientific or mathematical approach because I found too many conflicts in the data to make averaging of all data useful.

*For you Aussies:  http://en.wiktionary...entucky_windage

**For those from Kentucky: http://en.wikipedia....i/Least_squares

There is other data that shows much better responses for Gleevec, but I did not rely on it since it does not line well up with other studies.  An example would be the GIMEMA study.   But there were exceptions such as the Tasigna PCRU figures which are significantly better than Sprycel, which seems to have some reality behind it (possibly due to the twice daily dosage and longer half life), so it was not changed.  There are also small studies which provided useful response data for comparison purposes, but might not be acceptable by itself due to sample size.  Long term data is not yet available for Sprycel or Tasigna, so only time will tell whether they are superior to Gleevec over the long term.

For your own case, you are responding well ahead of the data.  Higher dosage of Gleevec (800mg) might produce faster results, but maybe at a cost to quality of life or ability to stay on the drug.  You could ask your Onc if you could try 600/800 every other day.  But if you ever needed to take a drug break in the past, then increased dosage would not be a good idea.



#10 Tedsey

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Posted 18 September 2011 - 03:34 PM

Dear Trey,

I assume that "stalling" and/or numbers (PCR) that remain the same over time would not necessarily indicate a "poor response" (fingers crossed here).  I am almost at the two year mark for dx, but I am only 1 year and 2 months on S.  On G, my last 3 PCRs stalled at 9 months.  And I did not get to CCyR then, (but my my cytogenics--remember, no FISH ever in my history, was at 10.5% at 9 mos. compared to unknown at dx---I can only assume it was 100% or near).

In my case, the side-effects made my life a living hell (which I will consider them "severe anemia" and neutropenia from G).  The side effects were probably the main reason for my switch to S, despite a slow response on G.  And I likely would not have reached CCyR at 1 year on G, (I agree, G is an excellent drug, but wasn't the best match for me).  After 3 months on S, I got the miracle response of CCyR.  And 3 months later I dropped 1/2 a log.  At almost at a year and 2 months on S, I am showing signs of "stalling" again.  But we shall see.

Would it be reasonable to feel secure over slight fluxes up and down at my non-MMR level, but relatively stable numbers?  Can I be content at CCyR if that is all I can get?  Would you think a change to Tasigna (which I kinda loathe taking because of the complexity of dosing) would be worth a try next August, (my 2 yr mark), if I don't reach very close to MMR at 2 years?  64% for MMR on S is a pretty impressive figure at 2 years.

I am totally holding on to the hope that stable is good.  And if CCyR is all I can ever get on whatever drugs I take, I hope with all my might, they will buy me time until the next best thing(s) come along.  And, of course, I hope it is a cure for all of us, or very clear data that people with CML, at any age, will not have compromised life-spans due to the disease.

Thanks for putting this is perspective for us.

Teds      



#11 Trey

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Posted 18 September 2011 - 04:49 PM

Teds,

You have made good progress in spite of the low blood counts issue.  The stats I posted show that you are somewhere in the middle of the pack by response.  CCyR is good, and if CCyR continues, then all is well.  Sprycel seems to be working well overall and you are regaining some blood quality.  That should continue, even if slowly.  And you have done well (not great, not perfectly, not amazingly) despite hardship.  Most often doing well is good enough.  And if "well" is stable over the long term, then well will eventually become "better than well", and probably even eventually will become "great".

You asked about "stalling out".  That is not a valid concept.  A person has one of three responses: 1) improving response, 2) stable response, 3) loss of response.  If you call "stable" by a name like "stalled out", then you have the wrong perspective.  This is not a mind over matter issue, it is a substance issue.  Fluctuations are the norm for PCRs, and most people do not see a linear decline in PCR numbers unless they go to zero very quickly.  So PCRs will bounce around and go up and go down and go sideways.  But it is the PCR trend that is important.  An individual PCR may be the same as the last one -- is that "stalled out"?  No, it is stable.  If a PCR goes up a little, does that demonstrate a loss of response?  No, it is that PCRs jump around, and they are not so accurate anyway (about 1/2 log accuracy), so either repeat now or wait for the next one to assess the trend.  If a person has a large jump in PCR and also loses CCyR, that PCR should always be repeated right away to see what the trend shows.  If the large jump in PCR is actually a trend, then action is required right away, usually changing drugs.  (Note that a 1 log increase from extremely low PCR levels does not constitute a "large jump".)  So a stable response can last for a period of time, but then will usually begin the downward trek again.  Most often, truly stable does NOT turn into loss of response.  The 10 years of IRIS data shows that those who were truly stable most often developed a better and better response over time, even if slowly.  The IRIS group gets more MMRs and more PCRUs each year, even after 10 years.  So tell me, were these people "stalled out" for years, or were they "stable"?

It is human nature to always want "better", especially when it about something important.  And we should want "better".  I wrote this posting to help patients see that although there is always a "better", most people live in the realm of "good enough", and "good enough" gets the job done except in rare instances.

I would add, however, that if someone is taking Gleevec and the response seems to be "stable" over a longer period, there is nothing wrong with switching to another drug to see if a faster response can be gained.  There is generally nothing wrong with switching drugs just to see what happens, and there does not need to be some big issue in order to justify a switch.  These TKI drugs are tools, and the best tool should be used.



#12 momruns

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Posted 18 September 2011 - 07:29 PM

Trey,

     Thank you as always for your information.  Maybe it is because I am a nurse or just because I want this over and I know its lifelong but I want the perfect results now or I think something is wrong.  As I wrote before and you answered, my numbers went the other way a little bit.  You did state "trend" is the issue not one blood work result.  Posting this lets me know I am still okay.  I just get a touch of anxiety with each blood work, I think having you and the people on this site telling me "relax" and we will all get through this is huge.

Loreta



#13 Shalom

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Posted 18 September 2011 - 08:38 PM

Can somebody help me with my results of my PCR test that I have in my documents everybody can see it, Trey can you help me and explain me where my .034 % came up from? I don't see that number and I don't knwo how to get it.

Thank you all

Hopefully some can help me to understand this document I really want to learn.



#14 Trey

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Posted 18 September 2011 - 09:06 PM

You labeled it as FISH but it is a PCR.

The result on your report says 3.5 x 10-4 

The exponent "-4" means you need to move the decimal point 4 places to the left, so the number becomes .00035  

Since PCRs are expressed as a percentage, you need to take the .00035 x 100 which equals .035%

So your PCR result is .035%

Ask your Onc to tell you what the log reduction is.



#15 WoofWoof

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Posted 18 September 2011 - 09:23 PM

Trey- great work as usual, thanks! Couple of quickie questions:

Did you include data that we here have provided?

What about those that never acheive an "complete" response as you define it?


I have cancer but it doesn't have me


#16 Shalom

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Posted 18 September 2011 - 09:32 PM

Trey,

You are the best I was doing it wrong 3.5 x 10-4 (6)  = 21 thats why I was compleately confused but now I know how to do it. The problem is that sometimes I go to lab test and 2 hours later I see my Dr. for results but sometimes still pending and what she only do is to tell one of the nurse to sent it to me via e-mail. Thats why I want to learn how to interpret all this results.

Thank you Trey



#17 Guest_billronm_*

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Posted 18 September 2011 - 09:36 PM

Dear Loreta,

I am 4 years since dx. And it's quite normal to get nervous every month when we get our bw. So consider yourself normal. I hope your doing well and cutting back on your hours at work. We do have to slow down a bit our immune system isn't as

strong as it was before, at least that's what I've been told. 3 weeks after my dx I was in the hospital with pneumonia for 5 days.And a temp of 103 the pneumonia cleared up fast but we never did figure out what was causing my temp. I got a pneumonia shot a couple months later and I've been doing pretty good since then.  I'm just down the road stop in for coffee anytime it's an open invite.

                                                                                                                          Take Care Billie



#18 Trey

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Posted 18 September 2011 - 09:52 PM

Woofer,

I did not use any data from people here.

Assuming "complete" response means PCRU, then the answer is that PCRU is not a requirement for long term good response.  But it seems that if someone continues to respond to drug therapy, they will have a continual deepening of their response over the long term.



#19 Guest_billronm_*

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Posted 18 September 2011 - 10:44 PM

Dear Trey,

Once again I thank you for that info, even I understood a bit of it.As I told you before after over 3 years on Gleevac my bcr-abl was 0. was still having gi issues on G. So I took a 5 week break and then started on 100mg of Sprycel what a difference for me much better no gi issues. But since going on Sprycel my anemia was getting worse every month. He lowered my Sprycel 100mg one day and 50mg the next day. That's the best bw I've had since going on S my anemia stayed the same it didn't go any lower than I started S. My iron was 3 and it was supposed to be 20 I was told. So I was scheduled for 5 iron infusions 1 time a week for 5 weeks. It was no big deal just tedious. Last Monday I had infusion #4 and I had a reaction hands and feet swelled up. So my onc canceled my last treatment,which would have been tomorrow. On Tues I get bw cbc,iron ferrous, and bcr-abl. Not quite sure what all that means. I see my onc on Friday. But I did notice I started feeling a bit better after those first 3 infusions. #4 not so good plus put on steroids for 3 days.The infusions only last about 3 days but I don't feel so tired or depressed I have some energy and my face isn't pasty white. Everyone noticed a big difference in me. Well I guess no more infusions.On to the iron pills. I've read they make you sick and a lot of people can't take them. Hopefully that won't happen to me. Have you heard anybody elses story similar to mine? Is there anything else out there to bring your iron level up? I think my iron has been low for quite a few years even before cml it took me 4 years to convince my onc that I wasn't just tired I knew something else was wrong but nobody would listen to me.Most people don't have low iron but at least our docs should run that blood test at least once.

Do you think another reduction in Sprycel will help me and is there more than 1 iron pill to try? Those few days after my infusions I felt better than I have in at least 20 years. I was always told it was depression. Can you give me some advice on what questions I should ask my Onc on Friday.  Thank you Trey  Sincerely Billie



#20 jjg

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Posted 18 September 2011 - 11:56 PM

Trey,

Thanks for the education: Having lived briefly in Georgia I thought "Kentucky windage" might have something in common with the male "engineering" phrase: "pissing in the wind", but I see now that it is a method of more substance.

I don't think we should involve PhilB in the discussion if he is going to expose the butt kicking beauty of maths. Although when it comes to numbers there is a particular beauty to the number 0 that we are all hoping to experience.

Thanks for your advice re 600/800 G. I've never needed, or come close to needing a drug break. When my body recovers from the shart combination of antibiotics for a sinus/chest infection and gleevec I'll raise the matter with my onc.

Billie,

I'm glad the iron made you feel better but sorry it was just for a short time. I've had mild iron issues all my adult life but not to the extent you describe. One time after avoiding docs for a year my iron was down to 2 and I had an iron infusion, but just the one infusion, it took 8 hours and lasted for many months. Now I just have regular iron injections - maybe 3 or 4 a year. I remember being told that the iron infusions or injections take a few days to kick in so for the effect to be all gone in 3 days is disappointing. I had the infusion to avoid needing a ridiculous number of injections. Do you know if after having a reaction to the infusion you can still have injections? Sorry I don't know you history on this board, have they checked you out for celiac disease or internal blood loss?


Dx Dec 2010 @37

2x IVF egg collection

Glivec 600 & 800mg

PCRU March 2012

Unsuccessful pregnancy attempt - relapsed, 3 months interferon (intron A), bad side effects from interferon

Nilotinib 600mg Oct 2012

PCRU April 2013, 2 years MR4.5 mostly PCRU with a few blips

April 2015 stopped again for pregnancy attempt (donor egg), pregnant first transfer, 0.110 at 10wks, 2.1 at 14wks, 4.2 at 16wks, started interferon, slow dose increase to 25MIU per wk, at full dose PCR< 1 for remainder of pregnancy

Healthy baby girl Jan 2016, breastfed one month

Nilotinib 600mg Feb 2016

MMR May 2016

PCRU Feb 2017





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