I'd really appreciate some help with a difficult case.

47 year old female, CML diagnosed 2009, b2a2 and b3a2 transcripts, commenced TIDEL II
May 09: Commenced Glivec 600mg/d but dose increased to 400mg bd due to low Day 22 trough level
Aug 09: achieved bcr-abl 0%
Nov 09: bcr abl 0%
Dec 09: bcr abl 0.008%
Mar 10: bcr abl 0%
Mar 10: bcr abl 0%
May 10: bcr abl 0.003%
Sep 10: 0.03%
Oct 10: bcr abl 0.11 – mutation analysis G250E 60%/Y253H 50%
Nov 10: bcr abl 0.17 – G250E 80%/Y253H 25%
Switched to nilotinib 400mg bd, fall in bcr abl in Nov and Dec 2010 but
Jan 11 bcr abl 0.21% with mutation analysis showing Y253H 100%.

Feb 11 Withdrawn from TIDEL II trial. Started dasatinib 100mg/d
Mar 11: bcr abl 0.11%, dasatinib increased to 70mg bd
Jun 11: bcr abl 0
May 12: bcr abl 0
Aug 12: bcr abl 0
Nov 12: bcr abl 0
Apr 13: faint pos
Jul 13: bcr abl 0
Oct 13: bcr abl 0

Bcr abl 0 throughout 2014 and 2015
Sep 15: dasatinib dose reduced to 100mg/d
Mar 16: bcr abl 0
Jun 16: bcr abl 0. Dyspnoea developing over around 6 months. Found to have large bilateral chylous effusions. Dasatinib ceased.
Jul 16: bcr abl 0
Aug 16: bcr abl 0.0015%
Sep 16: 0.015%, awaiting mutation analysis

What would people do here? Go back on nilotinib, go to ponatinib directly or consider other options?

Thanks for advice.

Assuming these mutations are not detected now as you have indicated last detection was 5 years ago, then nilotinib may have some merit short term, however I doubt it would be a stable response. We did publish a paper (Parker et al) showing that patients who developed a mutation which became undetectable on different TKI therapy tended to get that mutation back if they returned to the drug that they were on when the mutation emerged. I suspect that is what will happen if you give her nilotinib again – but it might take a while (assuming that the mutation is not detectable now) which would allow other options to open up.

Another option would be to give her steroid cover (prednisolone 25 mg/day, gradually reducing) and then restart half dose dasatinib once the effusion has completely or almost completely resolved. This assumes her lung function is satisfactory now. I suspect this would not be successful given the chronicity of her symptoms but the effusions don’t always recur.

Bosutinib might be a good option but it is not currently available in Australia.

Ponatinib would probably be effective at 45 mg/day but the safety profile is concerning with vascular events quite frequent in vascular high risk patients. Even if she has no major risk factors for vascular events, the risk of a devastating event is still present, although the risk is not high – probably less than 10%. Ponatinib at 30 mg/day is probably the preferred dose in this setting but there is no proof that it is safer or as effective as 45 mg/day. I think ponatinib is quite hard to justify in the current setting given her good molecular response.

The other possibility is the allosteric ABL inhibitor ABL001. The phase I trial is looking very promising. It is a remarkably well tolerated and has been quite active, particularly in intolerant patients. Caveats are that it has no track record against these mutations. The trial is currently running in Adelaide.

I guess there is a small possibility, given the duration of her deep molecular response that she won’t lose MMR while off therapy and you could simply watch her closely and hope that she achieves treatment free remission. This is not a recommended course of action given her past history of resistant disease, in particular I would not feel comfortable leaving her off therapy if she has any evidence of molecular positivity.

So in summary all of the options above are worth considering, but none are ideal for the reasons stated. My preference would be ABL001 if the patient was comfortable about entering a Phase I trial with the uncertainties regarding long term safety and efficacy implicit in a first-in-human study.

Given that this is an Australian patient, Tim has given a reasonable lay of the land given the Australian options and I agree with him in general. A couple of comments to bring the perspective a little more global in terms of options. I think that using imatinib or nilotinib will eventually result in re-emergence of the mutation, even if not evident at this time. Most of the world does not have access to the ABL001 study and even if they do, it is a study with all the limitations that Tim raised. What can be done in the non-academic non-research world. The first thing here is to get rid of the effusion. I have one slight concern here. Most dasatinib caused effusions tend to be exudative but not necessarily as described. In truth, I rarely tap these, so we do not have a perfect picture of what they are in all circumstances. The fact that this is chylous is somewhat intriguing and I would be sure that there is not something else going on unrelated to cml and dasatinib. My protocol to getting rid of them is to used a combination of furosemide and spironolactone (40/50) and give it a couple of weeks before going to prednisone. I find that if I have to go to prednisone after 2-4 weeks, it usually takes a good dose (1mg/kg) for a couple of weeks. If this is the first effusion, I would re-challenge at dasatinib 50mg per day. Most patients do not need 100mg and that dosing probably needs to be looked at given the French OPTIM data. With this mutation, bosutinib would be a good choice if available. Starting bosutinib or restarting dasatinib at a lower dose before getting rid of the effusion, will often result in worsening of the effusion. Although ponatinib would work, given the risk, this would be my absolute last choice and given the response would not go above 30mg and dose reduce early if the response is sustained.