8 yo girl diagnosed in July 2013 and was on Imatinib 340mg/m2 for 9 months, BCR ABL came down nicely and then doubled, mutation Y253H at 30% and changed to Dasatinib 30/7/14 at 60mg/m2 (50mg daily). Grew much better, all cytopenias improved and she felt much better as had been having intermittent abdominal pain, headaches, constipation and low energy levels. However had brief headaches without visual disturbance about every 1-2 weeks. 3 weeks ago she had a cold with otitis media, had course of antibiotics and better, then 1 week later developed bilateral frontal headache with blurred peripheral vision, despite low dose paracetamol she was still troubled 1 week later. Admitted under neurology had MRI/MRA/MRV and LP, eye review and all normal. Stopped Dasatinib and over 3-4 days headache settled. Also her BCR/ABL on dasatinib has gone down but seems to have levelled off at 0.11 (slightly higher than the 0.096, see below. She is now off Dasatinib for one week. My plan was to restart Dasatinib next week (2 weeks off) and see what happens but am interested in your opinion, should we lower the dose?

Next week I will do BCR:ABL and mutation analysis (is it worth it as she hasn’t met the criteria to do it but has stabilised) is she going to be a “persistently positive”.

Are there any other agents available?

This headache was clearly different from the previous headaches and more persistent, could it be Dasatinib toxicity due to antibiotics a week or so earlier, or the paracetamol? We did a level before stopping it which is frozen in biochemistry for when the assay is up and running. Both parents get migraine and this may be her developing it and it may be independent of Dasatinib, impossible to know.

The parents are considering a matched sibling donor transplant in October anyway so maybe we should do it earlier??

Hope you can help.

Quantitative BCR:ABL Results

Date & Result (IS)

Diagnosis 5/6/2013 CML

31/7/2013 = 3.5% (The 0.96% result is not IS)

28/8/2013 = 1.14%

9/10/2013 = 0.55%

16/12/2013 = 0.24%IS

19/3/14 = 0.37%IS

30/4/14 = 0.17%IS with mutation analysis
35INS mutation – no significance
10% Y253H – imatinib/nilotinib resistance

3/6/14 = 0.16%IS here, 0.40% IS Adelaide with mut Adelaide and Westmead found Y253H mutation 30%--

30/7/14 = Switch to Dasatinib 60mg/m2 = 50mg daily – BCR:ABL done as baseline 0.27%IS

10/9/14 = 0.11% IS (6 weeks Dasatinib) 10%mutation detected

15/10/14 = 0.099% IS (3 months Dasatinib) no mutation analysis

26/11/14 = 0.096% IS mutation analysis – not detected

25/2/15 = 0.11%

I haven't had a lot of problems with headaches associated with dasatinib but I guess that is a likely cause given the resolution when you stopped. I agree with your plan to cautiously restart dasatinib and see how she tolerates it. You may want to restart on a lower dose for a few weeks but I would aim to get back to full dose given the Y253H mutation and less than impressive molecular response so far. I am not too worried that she is not in MMR, it is more concerning that there doesn't seem to have been any reduction in BCR-ABL after about 9 months of dasatinib. I would recheck for mutations - those patients who develop mutations will not uncommonly develop new mutations or compound mutations on next line therapy. I think the transplant option is looking more attractive but I would want to be satisfied that I had given dasatinib every chance to achieve a deeper response first, so I personally wouldn't bring the transplant option forward (as long as she tolerates dasatinib on re-exposure). I would carefully review response dynamics after 12 months of dasatinib has been completed.

Regarding other agents - ponatinib is potentially available. It may be quite effective here but has proved to be quite toxic (pancreatitis and vascular events in adults) and I don't know about long term responses and toxicity in younger patients. The new ABL allosteric inhibitor from Novartis ABL-001 looks quite exciting but only in Phase I trials in adults at the moment. Nilotinib is not effective against this mutation. So options are limited if dasatinib doesn't achieve a deeper response.

I agree with much of what Dr Hughes has said. I have seen a number of dasatinib patients with headache and usually it is self-limiting within the first 2-8 weeks. This may actually be one of those cases where paracetamol may make things worse because of a potential drug interaction with the dasatinib, pushing up the levels and increasing the toxicity. Have you tried ibuprofen for the headache?
The response kinetics here are a little concerning and I would agree with a repeat mutation testing to be sure that a new mutation such as t315i has not developed. The one described should be sensitive to dasatinib, but new ones may not be.
In the event that dasatinib cannot be safely reintroduced, then choice of another drug will depend on whether there is a new mutation. If none, then you might consider bosutinib before ponatinib, given the lower potential adverse event profile. If however you find a new resistant mutation, you could consider bridging with ponatinib, but given the age of this individual and the potential duration of therapy, I would definitely favor consideration of an allograft if a donor is available.

Great comments from Drs Hughes and Lipton. Let me add a pediatric oncologist's view.

Neither bosutinib nor ponatinib has been tested in pediatric phase 1 study, therefore, we do not know a safe dose. Needless to say, they are not approved by health authorities. If the child was an adult-size teenager, we might try adult dose, but it would be hard for an 8 years old. She would be eligible for the phase 2 nilotinib study, which is currently open globally including in Children's Oncology Group. It would be an option without Y253H mutation.

For the option of HSCT, it is certainly encouraging there is a matched sib. In a German study by Suttorp et al, 5 year OS was 87+/-11% with matched sib donor which is from late 1990's to early 2000's. We also presented data from a large cohort of children with CML using CIBMTR data (ASH 2014). Patients who had HSCT from a matched sib donor in more recent years did better.

Nobuko Hijiya
Ann & Robert H Lurie Children’s Hospital of Chicago
Northwestern University Feinberg School of Medicine

Yes, she primarily uses Neurofen for headache, we only tried paracetamol this time as Neurofen was not effective. Thanks for all the useful input, Steven