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Imatinib Dose Reduction Starts

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Appointment this week at Countess of Chester Hospital, where the (new) consultant has agreed to follow Prof Clarke's proposed protocol that we cut my imatinib from 400mg to 200mg. I will have monthly BCR-ABL to check for any progression, and see them again at CoC just before Christmas. My PCR-ABl has been undetectable since 2009. If it stays at zero for a year on 200mg we will then stop. I will keep the forum posted on progress.  

All the best, Alistair. Exciting times for you

Best

Chrissie

Good luck!  I reduced more gradually - 300 mg for a year or more before going down to 200.  I noticed an immediate reduction (but unfortunately not total disappearance) of cramps and tiredness, and hope you have similar benefits.  I'm now on 4-monthly check-ups (next one in a couple of weeks), which also helps.

Olivia

Good luck Alastair - DESTINY results so far are cause for optimism that you will succeed in both dose reduction and then going off completely. I have also been undetectable since late 2009 and went on Destiny in 2014.  I finished Destiny in May - had a couple of blips in the results at one stage (which turned out not to be real) but other than that, with monthly testing for the first two years, then two monthly, I felt in safe hands.  Reducing to 200mg immediately reduced side effects to more or less nothing.  Richard

So 3 weeks into the reduced dose, it is a bit early to know much - my first blood test is 10 days away. However I've not had a significant attack of cramp, and the flatulence issue seems to be reduced. It hasn't helped that I started a cold at the same time as reducing the dose, and that lasted 10 days. Out walking the dog today, my wife commented I was walking faster than usual, and I walked straight up a hill where I have needed a rest half way up every time since we started doing this walk last year. Hadn't anticipated that impact, and makes it even more worth trying. 

I, too, am on the reduced dose of Imatinib down from 400 to 300 mgs - and what a difference. I had a weight problem in that it just refused to budge despite gym, swimming walking,fitness classes etc etc. Now it's shifting. More energy, less puffing when walking up one of the many Devon hills around here. I went onto 300mgs in June and am still holding MR4 so pleased after my DESTINY failure on half dose.

Are you still holding remission on 200mgs, Olivia?

Best

Chrissie

Hi Chrissie

No, I'm back up to 300 mg as my last couple of PCRs showed a slight rise.  I don't notice much difference in side effects, though I did have an eye bleed - very unusually for me - almost as soon as I went back to 300.  Perhaps I can get back down again some time, I just hope I don't have to go back to 400 mg.

Thanks for asking!

Olivia

Hi all. Just had the result of my PCR three months after reducing my imatinib to 200mg from 400mg. Still 0.00% so all good.

Good luck to all.

Alastair

Fantastic news for you. You must be delighted.

Are you planning on dropping lower than 200mg any time soon?

Well done!  Though we all know it's not due to any particular effort on our part, except for remembering to take the pills!  But I still send congratulations and hope you continue to eb well

Olivia

Thank you very much for sharing your results.  We are baby steps into Imatinib and we find this so encouaging that it can be done.  We are having issues with side effects but still hoping that we don't have to change to another TKI.  We will find out next week with our 3 months BCR-ABL1 results.   A lower dosage sounds wonderful so congratulations.

Would you mind sharing with me when you started Imatinib? 

Thanks, and all the best.

Tim and Michelle

Thanks for all good wishes.

David, the plan is to stay on 200mg for a total of 12 months (i.e. another 8 from now). Prof Clarke's protocol says to ignore any results less than 0.1% through this period. If all is good I will stop in September and continue to be tested monthly for the first 6 months.

Tim and Michelle, I started taking imatinib in the spring of 2007. Initially 400mg, but I have always had a very low wbc ( as I detailed on another thread recently) and I went down to 200 mg at the end of 2007 for about 6 months. PCR progress stalled so went back to 400mg and achieved log 3 in 18 months, and undetectable 3 months later.  

Alastair

Alastair, thanks for keeping us updated as to your PCR results now you are on a reduced dose of IM. The rational behind the Destiny protocol differed from other stopping trials - e.g. STIM, Euroski -

by including a de-escalation (dose reduction) phase in the first year. The thinking behind this was, and still is, that most CML patients who respond well to TKI therapy (with molecular responses at 0.1% -MR3 - or lower) over the first few years of therapy, will be able to maintain a molecular response in spite of a dose reduction.

If most 'good responders' can successfully halve the recommended dose with out losing MR3 (0,1%), then there is now good evidence that side effects are diminished, with an improvement in quality of life.

DESTINY has had excellent results and It seems has proved that although the percentage of patients eligible to stop and achieve TFR is very small (between 15-20% of good responders), dose reduction represents a pragmatic and positive approach towards dealing with TKI side effects for the majority of patients who will need to continue with therapy over the longer term. 

Wishing you well, and hope you will continue to maintain your MR over the coming months.

Best wishes,

Sandy

Alastair,

Best of Luck on your dosage reduction 

My own CML history

02/2010 Gleevec 400mg
2011 Two weakly positives, PCRU, weakly positive
2012 PCRU, PCRU, PCRU, PCRU
2013 PCRU, PCRU, PCRU, weakly positive
2014 PCRU, PCRU, PCRU, PCRU (12/07 began dose reduction w/each continuing PCRU)
2015 300, 250, 200, 150
2016 100, 50/100, 100, 10/17 TFR
2017 01/17 TFR, 04/18 TFR, 07/18 TFR 0.0012, 08/29 TFR 0.001, 10/17 TFR 0.000
2018 01/16 TFR 0.0004 ... next quarterly PCR 04/17

In hindsight I should have started my dosage reduction two years earlier; it might have helped minimize some of the longterm cumulative toxic effects of TKIs that I am beset with.

longterm side-effects Peripheral Artery Disease - legs (it's a bitch); continuing shoulder problems, right elbow inflammation. GFR and creatinine vastly improved after stopping Gleevec.

Cumulative Gleevec dosage estimated at 830 grams

Taking Gleevec 400mg an hour after my largest meal of the day helped eliminate the nausea that Gleevec is notorious for.

Buzz

Hi folks, just back from the latest appointment at the hospital, now approaching 6 months into reduction from 400mg Imatinib to 200 mg.

BCR ABL Results

Dec 0.000%

Jan 0.000%

Feb 0.005%

Prof Clarke's protocol from the trial says don't worry as long as results are less than 0.1%. So still a factor of 20 below any need to go back to 400mg. Was at a friend's 60th birthday party last week and danced till 2 a.m. Not sure I could have done that this time last year.

Best wishes to all.

Smashing results! 

I'm always slightly wary of a 0.000% ... could just mean the test was poor, and not very specific. Whereas a really low, but positive PCR strangely gives me more comfort in some ways. I once got a 0.000% but it was from 0.02 just before, and 0.02 immediately after. I suspect a clerical error and it was someone else's blood!

David.

Good news Alastair. 

I think dose reduction is shaping up to be the way to go for the majority of patients who have deep and stable PCR results. As you know L'pool has a lab with a sensitive PCR methodology, so the odd BCR/ABL1 transcript or two is probably insignificant. As you may or may not know, my PCR results were negative (0.00%) for some years post transplant... then when HH Lab set in place a more sensitive PCR test, suddenly I started seeing results with low positive transcripts. This has remained the case for the last 4 or so years with my results always stable at 0.002% - sometimes 0.001%. this number is very difficult to quantify, so I pay it no mind as it remains is a stable result. 

I wish you well with your half dose regime - who knows you might be able to reduce even further. To me, low dose TKI treatment, wherever possible, is a far more realistic proposition than TFR for a majority with stable MR..... with dose reduction It seems that you can remain stable at MR3 (0.1%) or lower which means many more people (who are not good candidates for TFR) will be able to reduce their side effects and have a much better quality of life in the longer term.

In my view, until we understand the mechanisms behind why a minority of patients with stable deep molecular response (DMR) are able to stop therapy without losing their MR, dose reduction is a much more realistic goal. 

Sandy

 

 

Progress for one, Progress for all!

Romo

Hi  Alastair,i   have been on 400 imatinib for a year + RECENTLY gone down to 300 as I find great difficultly sleeping  , has anyone else had this trouble do you know,  also joint pain , listless, + exhausted.

I was looking for info on the cml  trial but can't find anything. 

 Regards  Dawn

Dawn, I have also been on Imatinib 400 for a year, began the day of my presumed diagnosis on April 7, 2017. Diagnosis was confirmed within a week or so after PCR test. My WBC was 280K so it was good that I got started right away from an inventory at our hospital pharmacy. I do share all those side effects you mention. It seems that I am able to sleep during the day by napping but not so well at night! Doctor recommends staying as active as I can and also yoga for the joint pain. I enjoy hiking but it does seem to take longer (several days) to recover from anything strenuous. (I am 55.) Yoga does seem to help, for both body and mind. Waiting for my 12 mo. PCR results any day now. Have not talked with doctor about reducing dose but I will ask at next visit in 3 months. Do you feel better on 300? Thank you and good luck. Justine

Hi Dawn & Justine.

Sandy knows more than I do but I can say the trials on dose reduction were based on people who had been taking imatinib longer than it seems you both have been. In around 1 year getting to below 0.1% BCR ABL or close to it is a good result, and most people I'm aware of who have reduced dose stabilised at those low levels for several years before trying to reduce. There is research which shows that different people on imatinib have large variations in blood concentration of the drug, for reasons we don't fully understand. For those who get a high blood level, dose reduction may be a good option. If you are having bad side effects you can ask your consultant to check your blood or serum level. Kings College developed a new way of doing this test a few years ago, but it is not widely used. I have posted a link on here before; if you can't find it let me know and I'll look it up.

Hope this helps

Alastair 

Dawn I've just read your reply to the thread on the conference and it sounds like you need to change something. Assuming you are UK based I suggest you ask your consultant to get your blood imatinib levels checked.Details of a test offered to NHS hospitals through King's College are on this link  One of the tabs in the middle of the page gives a link to the request form. There was research published last year that shows that women seem to have a higher serum level of imatinib than men.There are reasons for this which are too complex for me to explain (and I have run a toxicology lab). If the side effects from imatinib are so severe and the level isn't too high perhaps a change of drug might be the way forward. 

Dear Alistair,

Thank you for your reply .I am in Nottingham + go to City hospital next week for bloods ect.  will try to speak to doc then . I could cope with the days if I could sleep at night. my gp  says he can't help me  that any sleeping tabs. are addictive + don.t work for very long.

Feeling  fed up ................  but 11 years + counting .  They gave me 2 weeks   gp  wouldn't listen to me  he thought my husband was beating me !   Anyway thankyou for being there for me.     Dawn

Hi Dawn, good luck with the hospital. I think I've picked up something wrong about your CML journey - you've said 11 years and counting in this post, but above you said 400mg Imatinib for a year, which I though was when you were diagnosed. If you want to share your treatment history and current PCR level it might help people understand and share relevant experience.

Congrats on your reduction, I have a question I to have been reduced to 200mg of gleevec and have noticed a slight elevation in creatinine clearance in the blood tests, did you have any issues with changes in other blood tests when you dosage was lowered. I had been on gleevec 400mg for 7 years prior to being reduced and Bcr test has shown a slight increase over the last 6 months from 0.00% to 0.03%

Hi Rich

I've not had any issues with other tests since I reduced, but I haven't looked at the creatinine numbers. I'm now seeing the registrar - I am threatening to send my consultant an invoice for training his staff on CML - but will have a look when I go back to see them next month. The consultant is still looking at the numbers, and if I wanted to see him or the results were gong the wrong way I would be seeing him very quickly. I will look at the creatinine numbers next month at my appointment and let you know if there is any change.  

All, just back from my appointment, 9 months after reducing from 400mg Imatinib to 200mg.

BCR-ABL Results

March 0.000%

April 0.001%

May 0.000%

So happily maintaining PCRU on 200mg. Appointment at end September and if this continues I will stop taking Imatinib and see if I am one of the lucky ones who can get to TFR.

Consultant was at a conference last week where he said there was an emerging consensus that dose reduction on TKIs and TFR was more likely to be successful the longer the patient has been in MMR.

Rich, sorry I forgot to look at the creatinine numbers!

This is terrific!  Even if TFR isn't ultimately the result, to prove (at least for yet one more person) that reducing a TKI by half can still maintain an extremely low and safe level is AWESOME for all of us!

So another visit to consultant today. PCR 0.002% on 200mg. I will continue to take 200mg imatinib for another 2-3 weeks until today's PCR result is back, and if still stable, I will stop taking imatinib and see if I am one of the lucky 70% who can acheive TFR. 

Hi Alastair,

Continuing good news for you. Just a note and to be clear, the 70% you quote represents the percentage of patients who have stable long term optimal response to TKi therapy i.e MR4 or lower by PCR (IS) rather than 70% of all patient in CP CML?

Congratulations and good luck.

Sandy

A (nowadays) rare post from me but this question and my recent PCR result (the two things are unconnected!) have prompted me to do so.

First, I didn't have the latest PCR result at the patient day in Birmingham - when I spoke, I mentioned that I'd had a few very small positives after going on DESTINY and beyond.  Well, the most recent PCR (early September) is once again 0.000 - so recorded as "undetectable".  This does rather suggest that the few small positives I've had in the past 3-4 years are probably not real (the highest number on the IS was 0.002% and my consultant suspects all the positives were probably artefact from the lab, not transcripts in my blood). I suspect she is right. Anyway, three years after stopping I appear still to be "undetectable".

Secondly, I now recall where I first saw the question of renal function, creatinine levels and imatinib. It must have been this post - mild impact on renal function of imatninib was also mentioned at the patient day as a potential side effect.  My creatinine certainly went up on imatinib, and my renal function numbers indicated mild chronic kidney disease CKD.  Indeed, I was investigated for this but it wasn't getting any worse so they decided it was all stable.  This was at a time before imatinib effects on renal function had been discussed (no one mentioned them to me).  

As I mentioned at the patient day, my renal function is now completely normal - creatinine levels are back where they should be.  I strongly suspect this is because I have stopped imatinib.  My experience supports a mild effect on kidney function of imatinib but one which reverses and indeed in any event seems to be pretty minor.  This is purely anecdotal and I mention it simply for the information of others. I've never discussed this with my consultant at the Hammersmith (it was another hospital that picked it up, when I had joint care).

Richard

I found the references:  TKIs Have Kidney Effects in Long-Term CML Treatment, by the network staff of Cancer magazine, July 31, 2015; and Imatinib Increases Serum Creatinine by Inhibiting Its Tubular Secretion in a Reversible Fashion in Chronic Myeloid Leukemia, by Vidal-Petiot et al, in Clinical Lymphoma, Myeloma and Leukemia, March 2016.

Hi everyone. Today is the first day in 11.5 years that I deliberately won't take any pills. 12 months on 200mg imatinib has passed uneventfully, highest PCR was 0.005%, so negligible. Next test is on 22 November, it will be interesting to see if I can stay at that level. Prof Clarke's data from Destiny showed that if the counts start going back up months 3-6 is the most likely time, so we will watch and hope, and see what other impacts (withdrawal symptoms or reduced side effects) arise. 

Fingers crossed.

Lots of luck with the next test, Alistair. I am watching/reading your account with interest as in Jan 2019 I will start the process, having held at MR4/4.5 on 300mgs since Feb 2016 - 200mgs for one year from Jan and then if still down at MR4/4,5 TF. My haem favours a more gently reduction to avoid withdrawal - hence the extra time on 200mgs.

I bet it seemed very odd not to have to take the tablet on the first few days. I know if I get that far I will be relishing my first grapefruit in over 10 years!

Looking forward to your posting after your next test,

best,

Chrissie

Best of luck Alastair! It must be a strange but exciting feeling!

Hi Alastair ,wishing you  all the luck in the world ,what a wonderful feeling hopefully no little pill to take ever again .We will all be following your progress with hope ,for all of us .Regards ,Denise.

 

 

 

Thanks to all for good wishes. Chrissie, I had not thought about the grapefruit question! 

I'd kill for grapefruit. I used to eat half of one for breakfast a few times a week! 

 

I've not tried grapefruit in the two weeks since I stopped my imatinib - I almost feel guilty given how much some of you are missing it while on your TKIs.

However I can report that despite a fairly strenuous three hour hike, with a good bit of uphill and eleven stiles, I have still not had an incident of cramp since my final dose. That's a significant change for me. First PCR sample will be taken next week.  

Hi everyone. Delighted to say my PCR from mid November is confirmed as 0.000% (7 weeks post stopping taking the pills). I knew it would be as the deal I have with my consultant is that I see him every two months and if the PCR result comes back and is not comfortably maintaining MMR he will contact me. Still feeling fine, no cramp, reduced flatulence and no "out of petrol" days in the last couple of months.

Interesting chat - he has some patients who don't want to consider dose reduction as they think he only suggests it to save the NHS money! The increased number of PCR tests costs more early on than the saving on generic imatinib. Also  discussed how quickly patients who achieve MMR should start thinking about dose reduction and trying for TFR. Several years gives the best chance of success - evidence suggests ideally 5 years.

Fantastic! Great to hear it’s staying stable, and even better that you are feeling better for it.

I have just reduced my dasatinib dose to 20mg, and hoping to see some benefit from that. I could do with all the extra energy I can get at the moment. I’m on 6-weekly PCR tests, but the economics of PCR vs drug is different with dasatinib. 

David.

Congratulations Alistair for TFR.....

YOUR PCR TEST...... EVERY MONTH / EVERY TWO MONTH /THREE....???

Every two months at the moment - will go to three months if the next test in March is at zero as well.

Just for information, when DESTINY ended for me (and I was still 0.000), I went to three monthly appointments. That was in May 2017.  I went to four monthly appointments in May 2018. Awaiting my latest PCR (sample taken last week so won't have the result for a couple of weeks from now I think - I expect it to be 0.000 or a small - probably false - positive eg 0.002). 

Hospital comfortable with this regime given that I've been essentially 0.000 since November 2009 and have been in TFR since May 2015 (ie when the DESTINY protocol meant I stopped imatinib completely).

Richard

Very good news.  Keep up the good work.  We're all rooting for you.  

Visit to clinic today PCR 0.03% from my test in January, which is the highest result I had during the half dose regime, which then returned to 0.000 six weeks later. Sticking with the Destiny protocol of ignoring any result below 0.1%; next test in June. My deal with my consultant is he will contact me if the test taken today gives a result over 0.1%. Now over 4 months into stopping imatinib. Onward.

Fingers crossed, Alastair! pulling for you to continue onward.

Great news Alastair. I am currently awaiting my first results after dropping to 200 mgs imainib in Jan 2019. Hope to be as lucky as you. Keep on posting,

Best

Chrissie

I ditto Chrissie and Scuba, Alistair.  On the edge of my seat!

That's awesome! Cheering for continued success : ) 

Such great news.  I'm elated for you.  Fingers crossed here as well

Alastair,

That is great news! I am hoping for continued success with your plans!

Just back from seeing the consultant. PCR 0.013% at March appointment nearly 6 months after stopping imatinib, having been 0.03% in January . WBC and neutrophil numbers stable and at and at top end of my range. All good. 

Great news indeed!!!  Watching for your next post.

 

Steff

Fabulous Alastair,you must be delighted well done ,

Great news, Alistair. Still holding MMR after the magic 6 months. I went down to half dosage (200mgs imatinib)  in Jan 2019 and mine are slowly rising 

Dec 2018 - 0.0049   

 Feb 2019 - 0.0071  

Apr 2019 - 0.0085

Awaiting the next result from bloods taken at GPs May 20th. Am currently being tested every 6 weeks.

The rises above are all very minimal but this may well indicate an upward trend. I am not changing anything until I lose MMR and reach 0.1. When I went down to 300mgs from 400mgs the same thing happened and I had a warning from the genetics lab that a trend had been noted but I hung on with the lower dose (with my haem's support)and regained MR4 so am following the same strategy for now.

Best to everyone,

Chrissiex

Hi, I've only just discovered this forum and read with interest your posts so thanks for sharing. I was diagnosed in 2010, started a full dose of Imatinib until 2015, then went onto the half dose on the Destiny trial and came off completely in May 2016. The levels were barely traceable in the first 2 years but in the last 12 months have been creeping up and as of last week went to 0.17 which unfortunately means I am due to start a full dose again this week. Hugely disappointed but from stats it appears the levels should drop back almost immediately which I hope for but its the side effects that fill me with horror, both physically and mentally. I've lost weight and focused on my fitness in the last 3+ years (regular running, 10k and 1/2 marathons) so I'm hoping my body can deal with the side effects better. I'm told by my Consultant that as I'm no longer part of Destiny or any trial treatment becomes a bespoke process of 'seeing what works' and I'm hoping to go to a half dose quickly - fingers crossed!

Good luck to all and great to read your stories and experiences. 

   

Well I just got my results from May 20th and yep I am now on 0.03% so still in MMR but no longer MR4. We have decided to hang in there on 200mgs and see what happens in the next few months - but I think I may well end up on full dosage once more. The same thing happened with DESTINY back in 2015.Disappointing, but hey I am still alive with a good quality of life and very little in the side effects department. Will post again with June's result once I get them.

Congrats to you lucky few in TFR,

Best

Chrissiex

Chrissie - consider switching drugs if you have to go back. Low dose dasatinib is a good alternative (i.e. < 40 mg).

Data suggests that rotating TKI drugs may do more to increase TFR success than staying on the same drug. Dasatinib works very differently than imatinib and will likely attack the resistant CML.

Just a thought.

Thanks, Scuba. Hope you are doing OK

Best

Chrissie

Hi Chrissie, I was worried about my 0.03 a couple of months ago but have gone back to 0.01 this time, so hope you go the same way.

Best

Alastair

Another visit to the clinic today. June BCR-ABL 0.02% - all other results fine (for me - I am still neutropenic, but in the range I have been for 30+ years). Consultant happy that all is stable; he will call me if there is an issue with the BCR-ABL taken today, but the next appointment is in 3 months, which will be 13 months since I last took imatinib.

Alestair

One year complete fully TFR ( fully drug free 365 days)???

Congratulations......

Any problem??? TFR year...

Hi Vikram, not quite one year yet - 10 months and counting. No issues at all. I had lost the side effects when I reduced from 400mg imatinib to 200mg. That felt like a much bigger change than going from 200mg to zero.

Alastair how long were you on Imatinub? I’m 4 years now. Over 3 years at 600, now at 400 PA is not wanting to change meds. Wants to continue at 400. Last test was .1  Thank you and congrats

 

 

I’m currently on imatinib for the past 8 years. Over the past year and a half been reduced from 400 mg to 200 mg. My bcr/abl has been at a 3 log reduction for the entirety of usage of imatinib and still holding strong according to my last test in July. My question is did your doctor recommend stopping medication completely due to side effects or to see if numbers were stable enough to start clinical trial for zero usage? Just wondering because I’ve actually noticed more side effects with the reduction from 400 mg to 200mg. Congrats by the way with being off the meds completely, gives me hope that one day I might not have to take medications anymore 

Hi,

In answer to your best wishes, here are my results after dropping from 300 to 200mgs imatinib with the hope of stopping in Jan 2020. From July 2017 when I dropped to 300mgs from 400mgs I was holding happily at MR4, bouncing around a bit between 0.008-0.001. This led myself and my haem to drop again to 200mgs in Jan 2019 - and since then my results were taken every 6 weeks as follows:

Dec 2018 - 0.004

Feb 2019- 0.007

Apr 2019 - 0.008

May 2019 - 0.03

July 2019 - 0.05

Now my options were: 1) carry on taking 200mgs and hope the immune system ( + daily brazil nuts!) wakes up and takes over knocking the "nasties" back down again  OR  2) go immediately onto the full 400mgs as  when I lost MMR on DESTINY in 2015  - although I hadn't lost MMR yet OR  3) go back to 300mgs and see what happens.

My haem left it down to me and I decided, as the 300mgs gave me no side effects, to return to 300mgs which I did on July 23 . I wanted to avoid having all the side effects again after so long off the full dose.Now awaiting the first blood test results since I started on 300mgs- but only 3 weeks of taking 300mgs so not holding my breath.

Half of me thinks I should have waited till I lost MMR before increasing the dose and the other half tells me I really wouldn't want the puffy, watery eyes, cramps etc again. Just hope the 300mgs does the trick.

Best to all

Chrissie

Hi everyone

Ray I was on imatinib at 400mg for over 10 years. Reduced to 200mg in October 2017, and stayed at around .005%. Stopped end of October last year.

Rich I am following the protocol of the Destiny Trial. I wanted to try reducing and potentially stopping to get away from side effects (flatulence, cramps, fatigue etc.) There are papers on e the site which show the results. The reduction to 200mg got rid of most of the side effects; it had a bigger effect than going from 200mg to zero.

Chrissie I'm entirely with you. I'd like to get back below .01%, and will look at supplementing to see if it helps. My consultant is happy that I'm stable at around 0.02%, but I'd like that second zero back. If it drifts up I will be more likely to want to start back on 200mg because the side effects at 400mg were much more significant. Waiting to lose MMR and then going back to 400mg is not where I want to be.