2 years gleevec 400mg and whats going on

At 18 months my consultant upped my imatinib to 600mg daily and that got me down to 0%. Now after 7 years he has no intention of reducing that dosage.

I'm currently on 600mg and levels are stable 0.13% they fluctuate up a little and down I've never reached 0.0 but my doc seems happy and is not concerned I've been on Glivec for 3 years. Started on 400mg and moved up to 600mg about a year ago cause my levels weren't low enough ad no side effects so far!

There is nothing wrong with you- it is just that imatinib is not as effective for you as it is for others. Generally speaking around 60% show an optimal response to imatinib (400mg) the other 40% are either intolerant, resistant, need a higher dose, or have a less than optimal response. You are responding well but patients now have choices and a 2nd gen TKI might well hit your residual disease harder taking you below 3 (0.01%) or even 4 logs (0.001%).
I think this is the level of bcr/abl where increasingly doctors want to see their patients get down to.

Having said that, we must not forget that there are many people over the last decade or so who have responded more slowly on imatinib 400mg, but have also maintained stable disease , even though they have not reached such low molecular levels.

I hope your next PCR shows a further zero so you can continue therapy with confidence for the long term. If you are stuck then it is probably the right time to change therapy to one of the 2nd Gen TKI available and given that you obviously have responsive disease then I am sure you will begin to see more zeros.

Sandy

I really understand your frustration with not reaching 'optimal' goals as outlined by ELNet and NCCN current guidelines.

What I would say is that ongoing data from studies of 2nd Gen TKis shows they have improved efficacy over imatinib.... scroll down home page for publications on this.
So although you are doing your best and at least are adhering to therapy, as you rightly point out, there are reasons that are not within our control that might cause a less optimal or slower response.
BTW. I recently read a shocking statistic for adherence to TKI therapy in CML:
"Patient adherence to treatment is poor with fewer than 25% of patients perfectly adhering to their therapy"
Only 25% of CML patients fully adherent! Hard to fathom.

Your reason for not wanting to move to another TKI makes sense in some ways, but as time and knowledge of how this disease behaves under TKi therapy advances, it might be that waiting to change therapy to a 2nd Gen TKI when you see bcr/abl levels increase (which is what I assume you mean when you say you are saving 2nd gen as a backup for the future) might not be the best plan.

A 2nd Gen TKi would more than likely affect a deeper molecular response (you obviously have responded to IM which proves you have responsive disease) and therefore into the 'safe harbour' of an MMR of more than a 3 log reduction = to 0.01% IS, and pref. even lower.

Side effect profiles of 2nd Gen TKis are not the same and certainly no worse than imatinib- in fact there is evidence of a general reduction in side effects.

Still.... your next PCR might well show a further drop which would indicate that you are a slow responder who will reach the optimal goal of MR4 to MR4.5 eventually.... even thought that might be frustrating.

I know some individual UK clinicians deny that there is good enough data to support the view that 2nd Gen TKIs are better than IM.
But, in my considered (lay) opinion- all the evidence says they are showing improved efficacy - especially in first line therapy.

I think we need to remember that a certain amount of financial pressure might be at play here, with some feeling the need to rationalise budgets at the expense of optimal therapy.
But that is another argument- although an interesting one- and for the moment some of us can only agree to differ with such a view.

Re: UK Patient Seminar.
This year it is being held in Glasgow- on Saturday 17th November. I am hoping to hear from Dr. Copeland soon regarding the logistical details.
As soon as I do I will post the address/agenda/hotel info etc. on this forum as usual.

I agree that to have CML as the sole focus of a days seminar is a real plus and I too thought Liverpool was a pretty good meeting- as was Cardiff last year.

We are pretty lucky in the UK to have the chance to attend this kind of seminar- not sure any other EU country has done this so far.

We have a lot to thank Profs. Apperley and Goldman who through the MRC CML Working party set up the first of this kind of Patient Seminar way back in October 2002, at the RCP in Regents Park London.
This was very early on in the history of TKI therapy for CML and has since proven to be a very forward looking step.
I remember that first day very well- and still have the agenda and profiles of all the doctors who presented.
Peter Capel gave a very relaxed and funny speech on behalf of CML patients. Peter was enrolled on the 106 trial of STI571 (imatinib) for newly diagnosed CML. Although Peter died last year from non-CML health complications, I will always remember his wit and humour on that day.

As I say.. we are very lucky here in the UK.

Sandy

Less than 25% CML patients are fully adherent to therapy......... yes that is pretty surprising and shocking- although we are all aware that some patients do take regular 'treatment breaks' for various and complex reasons. The problem with that strategy (and in the main it is mostly to do with side effects) is that if you are less than 90% adherent then it can effect the success of therapy.

This figure comes from clinical education programme 'Clinical Care Options Oncology' Chronic Myeloid Leukemia Treatment in Evolution: Patient Monitoring and Optimizing Therapeutic Strategies
Source: Chronic Myeloid Leukemia Treatment in Evolution By: Jerald Radich, MD

It is also near to the % given in a presentation on nonadherence by one of the consultants at HH.
below is a snip from one of the slides

Extent of Nonadherence to TKIs Imatinib:
Belgium: 1/3 of patients nonadherent; only 14% took all doses[1]
UK: 26% of patients had adherence ≤ 90%[2]
US: 31% patients had no imatinib for ≥ 30 days[3]
US: 41% patients had < 85% medication possession ratio[4]
US: 30% patients had ≥ 1 interruption of > 1 wk[5] Dasatinib and nilotinib, second line[6,7]

Few reports, with conflicting results

ref:
1. Noens L, et al. Blood. 2009;113:5401-1511. 2. Marin D, et al. J Clin Oncol. 2010;28:2381-2388. 3. Darkow T, et al. Pharmacoeconomics. 2007;25:481-496. 4. Wu EQ, et al. Curr Med Res Opin. 2010;26:61-69. 5. Ganesan P, et al. Am J Hematol. 2011;86:471-474. 6. Wu EQ, et al. Curr Med Res Opin. 2010;26:2861-2869. 7. Yood MU, et al. Curr Med Res Opin. 2012;28:213-219.

Sandy

Hi Nigel,

For practical everyday living purposes it is probably best to have a particular time when you take your medication- i.e with or after dinner or whichever meal (with imatinib) best suits an individual's daily routine. This also means that you do not forget to take your daily dose.

'Fully adherent' really means that medication is taken as prescribed. With TKIs it is pretty essential to keep the plasma levels constant. The half life of imatinib is, I believe, more or less around 12 hours, so to keep plasma level of imatinib high enough to expose the PH cells to an effective amount- i.e enough to shut down cell growth, you need to take it at roughly the same time each day. An hour or so either side is probably OK though.
With nilotinib you need to be pretty organised anyway because it is not taken with food so you have to fast for 2 hours before and 1 hour after. So a daily routine which fit in with your life-style needs to be worked out and adhered to.

With dasatinib you can be more flexible as food does not seem to have an effect on how it is metabolised.
BUT still you need to keep the levels up with some consistency.

With all TKis it is now known that if you regularly take less than 90% of your prescribed dose over time (say 6-12 months) you risk a less than optimal response and a higher chance of not reaching the desired goals - a higher risk of losing cytogenetic response or not reaching a deep enough MR etc.
I have read that the likelihood of a good CCyR is reduced down from over 90% to 50-60% likewise the probability of reaching MMR is much reduced if not ruled out altogether.

So.... if you miss more than 1 dose out of every 10 on a regular basis- you are considered to be not fully adherent. The shocking truth is, according to the %'s outlined in the several studies discussed in the above posts, that so many people knowingly or unknowingly take that risk.

Sandy

I too am shocked by the low levels of dose compliance reported in some of these studies. I take my 400mg IM at breakfast, but times do change (about 7.45 a.m. weekdays, can be 1-2 hours later at weekends). I have a solid routine at home, but I find if I'm away somewhere I can occasionally miss a dose, despite trying to remember to leave the pills beside my toothbrush. I suspect I have missed two or three doses in the last 12 months. (I have been PCRU for over 3 years, but took 21 months post dx to get to MMR)

I think dose compliance is key to planning dosing regimes - if people need to take pills twice a day there are double the number opportunities to miss a dose. I have emphasised this in some of the patient surveys I've been able to contribute to.

Congratulations on the extra zero! You must be so relieved. I understand completely why you do not want to change to another therapy if imatinib suits your life-style and is -gradually- getting your disease to low molecular levels. Hopefully your next PCR will be even lower ... 0.01% on the IS (international scale) = a 3 log reduction, and hopefully you will continue to get even below that with time.

BTW: the Spanish doctor you mentioned is David Marin (actually he is Catalan;o). He is a highly regarded CML expert clinician and I think is still head of clinical trials at Imperial College, Hammersmith Hospital. He is the lead on the recent publication that recommends an optimal response to first line therapy is to be at less than 10% PH+ by 3 months from diagnosis. But we must always remember that there are also people who continue to respond to imatinib but at a slower rate. As long as your PCRs show you have good and sustained response to therapy then you can be pretty sure you will maintain that over the long term.

Dr. Marin is a highly entertaining speaker as well as a very gifted clinician/researcher.

Hope to see you at Patient Seminar in Glasgow.

Sandy