if the anti PD-1 antibody trials are an option, then the other one to consider might be the dasatinib plus nivolumab study that is open in a number of centers
perhaps look at the most feasible option from a travel perspective

Thank you so much.

To clarify, her compliance has been great and we believe she is taking her medications.
She had a bone marrow in 2012 with complete cytogenetic response and no additional cytogenetic changes, with molecular measuring 1.21%.

I have spoken to the patient. She would be willing to make frequent travel to access treatment if it is required/possible. So, I guess anti-PD-1 antibody trial remains an option for her but last resort.

In regards to Ponatinib, she does not have any other medical conditions and we are in fact considering this being the next step.

I essentially agree with the detailed analysis and recommendations of my colleagues.

I guess you only increased the dose of dasatinib 3 months ago so you may want to wait to assess the response after 6 months. If there is no improvement I would consider switching her to ponatinib at the modified dose of 30 mg/day as long as she isn’t high risk for vascular events. If you achieved MMR I would modify the dose to 15 mg/day.

As David says there are two Phase I studies that would also be appropriate to consider if she was willing to travel frequently or move. Probably the anti-PD-1 antibody in addition to dasatinib would be the more likely to have an impact.

With regard to an allograft, I would get prepared but only contemplate this if the disease transformed (and you could re-establish a second chronic phase) or if she was refractory to ponatinib.

It is an interesting case. Here are my thoughts:
1) It seems to me that she does not have progressive rise in BCR-ABL and we shall look at the bone marrow cytogenetic if she is having ongoing CCyR or not.
2) Check for compliance and drug interactions
3) I will start tissue typing and consider her inadequate response as a “warning sign”.
4) In this case there are potentially three outcome
a. If her BCR-ABL vary in the same range (~1 to 1.8); I would suggest continue dasatinib. Consider switching to Ponatinib or ABL001 if and when available.
b. If she has progressive rise in BCR-ABL but maintains CML-CP then Ponatinib (unless ABL001 trail becomes available)
c. If Disease progression to AP/BC then allogeneic stem cell transplant

Although we like to see MMR or better, this is a woman with a stable CCyR now out more than 3 years since initial therapy. Given the limited options for therapy and the toxicity from other therapies, many of us would make sure that she is compliant and leave her where she is, unless there is a trial specifically to deal with this issue.

This 52 year old woman has had basically never achieved a sustained BCR-ABL <1% in the last 4.5 years, regardless of the treatment she’s been given, even at the high dasatinib dose of 140mg daily for over 1 year. No kinase domain mutation had been found, and I assume additional cytogenetic abnormalities had been sought and discounted. Compliance should be ensured and pharmacological interactions excluded (140mg dasatinib for 1yr+ in a 52 year old woman without side effects at full compliance…? Only 50-60% chance of that happening I would have thought…) Can you measure drug levels? Low level mutants may be present, of course, but if they are still at levels below that detectable by Sanger, they are probably not responsible for the intrinsic TKI resistance.

Options:
1. Bosutinib – very little chance of improving response
2. Ponatinib – PACE data showed CCyR of 48% at 2 years for patients resistant or intolerant to 2 other TKIs. It may be that the majority of responders in this study were intolerant patients Cost and long term toxicity are both prohibitive
3. add in interferon – worth a try if can be sourced
4. Enrol to the Phase I combination trial of dasatinib plus the Anti-PD-1 antibody – if it is available locally.
5. Wait for the trial of ABL001 combination with nilotinib to be available (Or ABL001 alone – not sure how active it would be in this case…)
6. Transplant – should be considered, but difficult to commit to in 2015. Would be less reluctant if she was younger and a sib donor was available.
7. Do nothing. Probably not as horrible as it sounds if the IRIS data is applicable, compared to TRM. The IRIS landmark data would suggest that even though this is a high risk situation, patients with BCR-ABL between 1-10% at 18 months could still be expected to have a transformation free survival of ~80%. This data may be not applicable to this case in entirety: Landmark analyses are not available for later time-points. Nor do we know the number of patients potentially rescued from AP/BC by a therapy other than imatinib, though this is likely to be small.

In the absence of Anti-PD-1, I would edge towards a transplant, followed a close second by do nothing and waiting for the ABL001 phase II.